Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

This application is a continuation of U.S. patent application Ser. No.17/004,841, filed Aug. 27, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/557,819, filed Aug. 30, 2019, now abandoned,which is a continuation of U.S. patent application Ser. No. 15/993,521,filed May 30, 2018, now abandoned, which is a continuation of U.S.patent application Ser. No. 15/219,208, filed Jul. 25, 2016, nowabandoned, which is a continuation of U.S. patent application Ser. No.14/694,965, filed Apr. 23, 2015, now abandoned, which is a continuationof U.S. patent application Ser. No. 13/830,926, filed Mar. 14, 2013, nowU.S. Pat. No. 9,045,475, issued Jun. 2, 2015, which is a continuation ofU.S. patent application Ser. No. 12/787,682, filed May 26, 2010, nowU.S. Pat. No. 8,546,399, issued Oct. 1, 2013, which claims the benefitof U.S. Provisional Application No. 61/181,203, filed May 26, 2009, eachof which is incorporated by reference herein in its entirety.

SEQUENCE LISTING

This application incorporates by reference in its entirety the ComputerReadable Form (CRF) of a Sequence Listing in ASCII text format submittedvia EFS-Web. The Sequence Listing text file submitted via EFS-Web,entitled “12655-168-999_SL.txt”, was created on Oct. 29, 2021, and is1,193 bytes in size.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity of Bcl-2anti-apoptotic proteins, compositions containing the compounds, andmethods of treating diseases during which anti-apoptotic Bcl-2 proteinsare expressed.

BACKGROUND OF THE INVENTION

Anti-apoptotic Bcl-2 proteins are associated with a number of diseases.There is therefore an existing need in the therapeutic arts forcompounds which inhibit the activity of anti-apoptotic Bcl-2 proteins.

Overexpression of Bel-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem.

Involvement of Bel-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, spleen cancer, and the like is described incommonly-owned PCT US 2004/36770, published as WO 2005/049593, and PCTUS 2004/37911, published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.Involvement of Bel-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, which are useful as inhibitors ofanti-apoptotic Bcl-2 proteins, the compounds having Formula (I)

wherein

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

G¹ is H, or C(O)OR;

R is alkyl;

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with R^(2A); R^(2A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with R^(3A); R^(3A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(4A); R^(4A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR⁷, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with R^(8A); R^(8A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with R^(9A); R^(9A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(10A); R^(10A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R¹²,OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹²,NH₂, NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with R^(13A); R^(13A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with R^(14A); R^(14A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with R^(15A); R^(15A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with R^(18A); R^(18A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with R^(19A); R^(19A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with R^(20A); R^(20A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²)₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²,SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl, which is unfused or fused with R^(23A); R^(23A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with R^(24A); R^(24A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(25A); R^(25A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with R^(26A); R^(26A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with R^(27A); R^(27A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with R^(28A); R^(28A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with R^(29A); R^(29A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with R^(30A);R^(30A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B)SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B) NR^(37B)C(O)R^(37B) NHS(O)₂R^(37B)NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B) NR^(37B)C(O)OR^(37B) NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B)NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B) C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B) C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, or R^(37C);

R^(37C) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with R^(38A); R^(38A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with R^(39A); R^(39A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(40A); R^(40A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are substituted (i.e.,if Z^(1A) and Z^(2A) are absent) or further substituted (i.e., if Z^(1A)and Z^(2A) are present) with R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹,CO(O)R⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹,NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹, NHC(O)NHR⁴¹,NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂,C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹, C(O)NR⁴¹SO₂R⁴¹, SO₂NHR⁴¹, SO₂N(R⁴¹)₂,C(N)NHR⁴¹, or C(N)N(R⁴¹)₂;

R⁴¹ is heteroaryl, which is fused with R^(43A); R^(43A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; which is unfused or fused with benzene, heteroareneor R^(43B); R^(43B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the cyclic moieties represented by E¹ and Y¹ together, Y¹ and B¹together, A² and B¹ together, A² and D¹ together, R^(1A), R², R^(2A),R³, R^(3A), R⁴, R^(4A), R⁶, R^(6C), R⁸, R^(8A), R⁹, R^(9A), R¹⁰,R^(10A), R¹³, R^(13A), R¹⁴, R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹,R^(19A), R²⁰, R^(20A), R²³, R^(23A), R²⁴, R^(24A), R²⁵, R^(25A), R²⁶,R^(26A), R²⁷, R^(27A), R²⁸, R^(28A), R²⁹, R^(29A), R³⁰, R^(30A),R^(37B), R³⁸, R^(38A), R³⁹, R^(39A), R⁴⁰, and R^(40A) are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five of independently selectedR^(57A), R⁵⁷, OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷,OC(O)OR⁵⁷, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷,NR⁵⁷S(O)₂R⁵⁷, NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷,NHC(O)N(R⁵⁷)₂, NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂, C(O)NH₂, C(O)NHR⁵⁷,C(O)N(R⁵⁷)₂, C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R¹⁷, SO₂NH₂,SO₂NHR¹⁷, SO₂N(R¹⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R¹⁷)₂,CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl,Br or I;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with R^(58A); R^(58A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with R^(59A); R^(59A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(60A); R^(60A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶²,NH₂, NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with R^(63A); R^(63A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with R^(64A); R^(64A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with R^(65A);R^(65A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³,R⁶⁴, R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two orthree or four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸,SO₂R⁶⁸, C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂,NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸,NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸,NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸,C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with R^(69A); R^(69A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with R^(70A); R^(70A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(71A); R^(71A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁷³,OR⁷³, SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³,NH₂, NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁷³ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstitutedor substituted with one or two or three or four of independentlyselected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH,C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, which are useful as inhibitors ofanti-apoptotic Bcl-2 proteins, the compounds having Formula (II)

or a therapeutically acceptable salt thereof, wherein

R¹⁰⁰ is as described for substituents on R²⁶.

n is 0, 1, 2, or 3;

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with R^(2A); R^(2A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with R^(3A); R^(3A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(4A); R^(4A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R⁶B), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR⁷, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with R^(8A); R^(8A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with R^(9A); R^(9A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(10A); R^(10A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R¹²,OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹² CO(O)R¹², OC(O)R¹², OC(O)OR¹², NH₂,NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with R^(13A); R^(13A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with R^(14A); R^(14A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with R^(15A); R^(15A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with R^(18A); R^(18A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with R^(19A); R^(19A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with R^(20A); R^(20A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²)₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl, which is unfused or fused with R^(23A); R^(23A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with R^(24A); R^(24A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(25A); R^(25A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z² is R²⁸, R²⁹ or R³⁰;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁸ is phenylene, which is unfused or fused with R^(28A); R^(28A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with R^(29A); R^(29A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with R^(30A);R^(30A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B)SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B) NR^(37B)C(O)R^(37B) NHS(O)₂R^(37B)NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B) NR^(37B)C(O)OR^(37B) NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B)NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B) C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B) C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, or R^(37C);

R^(37C) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with R^(38A); R^(38A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with R^(39A); R^(39A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(40A); R^(40A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the cyclic moieties represented by E¹ and Y¹ together, Y¹ and B¹together, A² and B¹ together, A² and D¹ together, R^(1A), R², R^(2A),R³, R^(3A), R⁴, R^(4A), R⁶, R⁶C, R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A),R¹³, R^(13A), R¹⁴, R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹, R^(19A),R²⁰, R^(20A), R²³, R^(23A), R²⁴, R^(24A), R²⁵, R^(25A), R²⁶, R^(26A),R²⁷, R^(27A), R²⁸, R^(28A), R²⁹, R^(29A), R³⁰, R^(30A), R^(37B), R³⁸,R^(38A), R³⁹, R^(39A), R⁴⁰, and R^(40A) are independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷,NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR¹⁷C(O)R¹⁷, NHS(O)₂R¹⁷, NR⁵⁷S(O)₂R¹⁷,NHC(O)OR¹⁷, NR¹⁷C(O)OR¹⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂,NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷,SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R^(57A) is spiroalkyl or heterospiroalkyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with R^(58A); R^(58A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with R^(59A); R^(59A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(60A); R^(60A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶²,NH₂, NR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶² NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with R^(63A); R^(63A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with R^(64A); R^(64A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(65A); R^(65A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NHR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³,R⁶⁴, R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two orthree or four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸,SO₂R⁶⁸, C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂,NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸,NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸,NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸,C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with R^(69A); R^(69A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with R^(70A); R^(70A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(71A); R^(71A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁷³,OR⁷³, SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³,NH₂, NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁷³ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstitutedor substituted with one or two or three or four of independentlyselected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH,C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI.

Another embodiment pertains to compounds of Formula (I) wherein A¹ is Nor C(A²) A² is H, and G¹ is H.

Another embodiment pertains to compounds of Formula (I) wherein A¹ is Nor C(A²) A² is H; G¹ is H, and B¹ is NHR¹.

Another embodiment pertains to compounds of Formula (I) wherein A¹ is Nor C(A²) A² is H; G¹ is H, B¹ is NHR¹; and D¹ is H.

Another embodiment pertains to compounds of Formula (I) wherein A¹ is Nor C(A²) A² is H; G¹ is H, B¹ is NHR¹; D¹ is H; and E¹ is H.

Another embodiment pertains to compounds of Formula (I) wherein A¹ is Nor C(A²) A² is H; G¹ is H, B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are

-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(2-naphthylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   5-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethoxy)nicotinamide;-   N-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-bromo-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-oxo-3,4-dihydroquinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-3-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   and therapeutically acceptable salts, and metabolites thereof.-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yl    oxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S,3R)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,3S)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[cis-3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide;-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[trans-4-(fluoromethyl)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclobutylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-2-oxopiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylazetidin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-cyclopropylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclobutylmorpholin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydrofuran-3-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(trifluoromethoxy)benzyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxaspiro[4.5]dec-8-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[cis-3-morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-fluoro-1-(methylsulfonyl)piperidin-4-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[3-(dimethylamino)propoxy]benzyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(E)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(Z)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dien-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   (2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholin-4-yl)acetic    acid;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   ethyl    4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)piperazine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(2-methoxyethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]piperazine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-(pentafluoro-λ⁶-sulfanyl)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(oxetan-3-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3R)-tetrahydrofuran-3-ylamino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(oxetan-3-yl)azetidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl}sulfonyl)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(3-furylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-chloro-6-[2-(tetrahydrofuran-2-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-methylpiperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(cyclopropylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-chloro-6-(2-methoxyethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(methoxyacetyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide;-   N-({5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(trans-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(cis-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(1,3-thiazol-5-ylmethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-chloro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl)phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,5-difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,4-difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-{[3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   methyl    2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholine-4-carboxylate;-   2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}phenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   (2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   N-[(5-chloro-6-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2,2-difluorocyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(2-oxaspiro[3.5]non-7-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-cyano-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2-oxaspiro[3.5]non-7-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   {[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methyl    pivalate;-   {[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methyl    butyrate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-cyano-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)morpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methoxymethyl)cyclohexyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-chloro-6-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;    and therapeutically acceptable salts, and metabolites thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compoundTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compoundCis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compoundTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compoundN-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compoundN-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which areN-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;

-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;    or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compoundN-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which areN-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to a composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositioncomprising an excipient and a therapeutically effective amount of acompound of Formula (I) or Formula (II).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I) or Formula (II).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient therapeutically effective amount of thecompound of Formula (I) or Formula (II) and a therapeutically effectiveamount of one additional therapeutic agent or more than one additionaltherapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letterswith numerical and/or alphabetical superscripts) and may be specificallyembodied.

It is meant to be understood that proper valences are maintained for allmoieties and combinations thereof, that monovalent moieties having morethan one atom are drawn from left to right and are attached throughtheir left ends, and that divalent moieties are also drawn from left toright.

It is also meant to be understood that a specific embodiment of avariable moiety herein may be the same or different as another specificembodiment having the same identifier.

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C_(x)-C_(y) alkenyl”means a straight or branched hydrocarbon chain containing at least onecarbon-carbon double bond containing x to y carbon atoms. The term“C₃-C₆ alkenyl” means an alkenyl group containing 3-6 carbon atoms.Representative examples of alkenyl include, but are not limited to,buta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of 2 to 4 carbon atoms and contains at leastone carbon-carbon double bond. The term “C_(x)-C_(y) alkenylene” means adivalent group derived from a straight or branched hydrocarbon chaincontaining at least one carbon-carbon double bond and containing x to ycarbon atoms. Representative examples of alkenylene include, but are notlimited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term“C_(x)-C_(y) alkyl” means a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₁-C₆ alkyl”means a straight or branched chain, saturated hydrocarbon containing 2to 6 carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, and n-decyl.

The term “alkylene” means a divalent group derived from a straight orbranched, saturated hydrocarbon chain of 1 to 10 carbon atoms, forexample, of 1 to 4 carbon atoms. The term “C_(x)-C_(y) alkylene” means adivalent group derived from a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₆ alkylene”means a straight or branched chain, saturated hydrocarbon containing 2to 6 carbon atoms. Representative examples of alkylene include, but arenot limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and—CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. The term “C_(x)-C_(y) alkynyl”means a straight or branched chain hydrocarbon group containing from xto y carbon atoms. For example “C₃-C₆ alkynyl” means a straight orbranched chain hydrocarbon group containing from 3 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited to, acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkynylene,” as used herein, means a divalent radical derivedfrom a straight or branched chain hydrocarbon group containing from 2 to10 carbon atoms and containing at least one carbon-carbon triple bond.

The term “aryl” as used herein, means phenyl.

The term “cyclic moiety,” as used herein, means benzene, phenyl,phenylene, cycloalkane, cycloalkyl, cycloalkylene, cycloalkene,cycloalkenyl, cycloalkenylene, cycloalkyne, cycloalkynyl,cycloalkynylene, heteroarene, heteroaryl, heterocycloalkane,heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and spiroalkyl.

The term “cycloalkylene” or cycloalkyl” or “cycloalkane” as used herein,means a monocyclic or bridged hydrocarbon ring system. The monocycliccycloalkyl is a carbocyclic ring system containing three to ten carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The monocyclic ring may contain one or twoalkylene bridges, each consisting of one, two, or three carbon atoms,each linking two non-adjacent carbon atoms of the ring system.Representative examples of such bridged cycloalkyl ring systems include,but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane,bicyclo[4.2.1]nonane, tricyclo[3.3.1.0^(3,7)]nonane(octahydro-2,5-methanopentalene or noradamantane), andtricyclo[3.3.1.1^(3,7)]decane (adamantane). The monocyclic and bridgedcycloalkyl can be attached to the parent molecular moiety through anysubstitutable atom contained within the ring system.

The term “cycloalkenylene,” or “cycloalkenyl” or “cycloalkene” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkenyl has four to ten carbon atoms and zeroheteroatoms. The four-membered ring systems have one double bond, thefive- or six-membered ring systems have one or two double bonds, theseven- or eight-membered ring systems have one, two, or three doublebonds, and the nine- or ten-membered rings have one, two, three, or fourdouble bonds. Representative examples of monocyclic cycloalkenyl groupsinclude, but are not limited to, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, and cyclooctenyl. The monocycliccycloalkenyl ring may contain one or two alkylene bridges, eachconsisting of one, two, or three carbon atoms, each linking twonon-adjacent carbon atoms of the ring system. Representative examples ofthe bridged cycloalkenyl groups include, but are not limited to,4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and1,6-dihydro-pentalene. The monocyclic and bridged cycloalkenyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “cycloalkyne,” or “cycloalkynyl,” or “cycloalkynylene,” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkynyl has eight or more carbon atoms, zeroheteroatoms, and one or more triple bonds. The monocyclic cycloalkynylring may contain one or two alkylene bridges, each consisting of one,two, or three carbon atoms, each linking two non-adjacent carbon atomsof the ring system. The monocyclic and bridged cycloalkynyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “heteroarene,” or “heteroaryl,” or “heteroarylene,” as usedherein, means a five-membered or six-membered aromatic ring having atleast one carbon atom and one or more than one independently selectednitrogen, oxygen or sulfur atom. The heteroarenes of this invention areconnected through any adjacent atoms in the ring, provided that propervalences are maintained. Representative examples of heteroaryl include,but are not limited to, furanyl (including, but not limited thereto,furan-2-yl), imidazolyl (including, but not limited thereto,1H-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl,pyridinyl (e.g. pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,1,3-thiazolyl, thienyl (including, but not limited thereto, thien-2-yl,thien-3-yl), triazolyl, and triazinyl.

The term “heterocycloalkane,” or “heterocycloalkyl,” or“heterocycloalkylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and zero double bonds. The monocyclic and bridgedheterocycloalkane are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quaternized. Representative examples of heterocycloalkanegroups include, but are not limited to, morpholinyl, tetrahydropyranyl,pyrrolidinyl, piperidinyl, dioxolanyl, tetrahydrofuranyl,thiomorpholinyl, 1,4-dioxanyl, tetrahydrothienyl, tetrahydrothiopyranyl,oxetanyl, piperazinyl, imidazolidinyl, azetidine, azepanyl, aziridinyl,diazepanyl, dithiolanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,oxadiazolidinyl, oxazolidinyl, pyrazolidinyl, tetrahydrothienyl,thiadiazolidinyl, thiazolidinyl, thiomorpholinyl, trithianyl, andtrithianyl.

The term “heterocycloalkene,” or “heterocycloalkenyl,” or“heterocycloalkenylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and one or more double bonds. The monocyclic and bridgedheterocycloalkene are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quaternized. Representative examples of heterocycloalkenegroups include, but are not limited to, 1,4,5,6-tetrahydropyridazinyl,1,2,3,6-tetrahydropyridinyl, dihydropyranyl, imidazolinyl,isothiazolinyl, oxadiazolinyl, isoxazolinyl, oxazolinyl, pyranyl,pyrazolinyl, pyrrolinyl, thiadiazolinyl, thiazolinyl, and thiopyranyl.

The term “phenyl,” as used herein, means a monovalent radical formed byremoval of a hydrogen atom from benzene.

The term “phenylene,” as used herein, means a divalent radical formed byremoval of a hydrogen atom from phenyl.

The term “spiroalkyl,” as used herein, means alkylene, both ends ofwhich are attached to the same carbon atom and is exemplified byC₂-spiroalkyl, C₃-spiroalkyl, C₄-spiroalkyl, C₅-spiroalkyl,C₆-spiroalkyl, C₇-spiroalkyl, C₈-spiroalkyl, C₉-spiroalkyl and the like.

The term “spiroheteroalkyl,” as used herein, means spiroalkyl having oneor two CH₂ moieties replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N.

The term “spiroheteroalkenyl,” as used herein, means spiroalkenyl havingone or two CH₂ moieties replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N and also means spiroalkenyl having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties replacedwith N.

The term “C₂-C₅-spiroalkyl,” as used herein, means C₂-spiroalkyl,C₃-spiroalkyl, C₄-spiroalkyl, and C₅-spiroalkyl.

The term “C₂-spiroalkyl,” as used herein, means eth-1,2-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₃-spiroalkyl,” as used herein, means prop-1,3-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₄-spiroalkyl,” as used herein, means but-1,4-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₅-spiroalkyl,” as used herein, means pent-1,5-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₆-spiroalkyl,” as used herein, means hex-1,6-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “NH protecting group,” as used herein, meanstrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenylmethyl, 2-nitrophenylthio, methanesulfonyl,para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl,naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl,para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl,benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl,succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl,1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group,” as used herein, meansbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determined by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.Furthermore, the invention contemplates the various isomers and mixturesthereof resulting from the disposal of substituents around an adamantanering system. Two substituents around a single ring within an adamantanering system are designated as being of Z or E relative configuration.For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. leNoble J. Org. Chem. 1998, 63, 2758-2760.

Compounds of this invention may contain asymmetrically substitutedcarbon atoms in the R or S configuration, in which the terms “R” and “S”are as defined by the IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.Compounds having asymmetrically substituted carbon atoms with equalamounts of R and S configurations are racemic at those carbon atoms.Atoms with an excess of one configuration over the other are assignedthe configuration present in the higher amount, preferably an excess ofabout 85%-90%, more preferably an excess of about 95%-99%, and stillmore preferably an excess greater than about 99%. Accordingly, thisinvention includes racemic mixtures, relative and absolutestereoisomers, and mixtures of relative and absolute stereoisomers.

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms having an atomic mass or mass numberdifferent from the atomic mass or mass number most abundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds that containother isotopes of these and/or other atoms are within the scope of thisinvention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄/D₂₀. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673(1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCTpublications WO1997010223, WO2005099353, WO1995007271, WO2006008754;U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421;7,514,068; 7,511,013; and US Patent Application Publication Nos.20090137457; 20090131485; 20090131363; 20090118238; 20090111840;20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of Bcl-2 inhibitors in binding assays.Isotope containing compounds have been used in pharmaceutical researchto investigate the in vivo metabolic fate of the compounds by evaluationof the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, non-radioactive isotope containing drugs, such asdeuterated drugs called “heavy drugs,” can be used for the treatment ofdiseases and conditions related to Bcl-2 activity. Increasing the amountof an isotope present in a compound above its natural abundance iscalled enrichment. Examples of the amount of enrichment include fromabout 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol%. Replacement of up to about 15% of normal atom with a heavy isotopehas been effected and maintained for a period of days to weeks inmammals, including rodents and dogs, with minimal observed adverseeffects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770;Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czajka D M et al.,Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-23%in human fluids with deuterium was found not to cause toxicity(Blagojevic N et al. in “Dosimetry & Treatment Planning for NeutronCapture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994.Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properties of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bond involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope at a site of metabolism orenzymatic transformation will slow said reactions potentially alteringthe pharmacokinetic profile or efficacy relative to the non-isotopiccompound.

Suitable groups for A¹, B¹, D¹, E¹, G¹, Y¹, L¹, Z^(1A), Z^(2A), Z¹, Z²,and Z³ in compounds of Formula (I) are independently selected. Thedescribed embodiments of the present invention may be combined. Suchcombination is contemplated and within the scope of the presentinvention. For example, it is contemplated that embodiments for any ofA¹, B¹, D¹, E¹, G¹, Y¹, L¹, Z^(1A), Z^(2A), Z¹, Z², and Z³ can becombined with embodiments defined for any other of A¹, B¹, D¹, E¹, G¹,Y¹, L¹, Z^(1A), Z^(2A), Z¹, Z², and Z³.

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, which are useful as inhibitors ofanti-apoptotic Bcl-2 proteins, the compounds having Formula (I)

wherein

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

G¹ is H, or C(O)OR;

R is alkyl;

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with R^(2A); R^(2A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with R^(3A); R^(3A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(4A); R^(4A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR⁷, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with R^(8A); R^(8A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with R^(9A); R^(9A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(10A); R^(10A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R¹²,OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹²,NH₂, NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with R^(13A); R^(13A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with R^(14A); R^(14A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with R^(15A); R^(15A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with R^(18A); R^(18A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with R^(19A); R^(19A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with R^(20A); R^(20A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²)₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²,SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl, which is unfused or fused with R^(23A); R^(23A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with R^(24A); R^(24A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(25A); R^(25A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with R^(26A); R^(26A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with R^(27A); R^(27A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with R^(28A); R^(28A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with R^(29A); R^(29A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with R^(30A);R^(30A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B)SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B) NR^(37B)C(O)R^(37B) NHS(O)₂R^(37B)NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B) NR^(37B)C(O)OR^(37B) NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B)NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B) C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B) C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, or R^(37C);

R^(37C) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with R^(38A); R^(38A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with R^(39A); R^(39A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(40A); R^(40A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are substituted (i.e.,if Z^(1A) and Z^(2A) are absent) or further substituted (i.e., if Z^(1A)and Z^(2A) are present) with R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹,CO(O)R⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹,NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹, NHC(O)NHR⁴¹,NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂,C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹, C(O)NR⁴¹SO₂R⁴¹, SO₂NHR⁴¹, SO₂N(R⁴¹)₂,C(N)NHR⁴¹, or C(N)N(R⁴¹)₂;

R⁴¹ is heteroaryl, which is fused with R^(43A); R^(43A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; which is unfused or fused with benzene, heteroareneor R^(43B); R^(43B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the cyclic moieties represented by E¹ and Y¹ together, Y¹ and B¹together, A² and B¹ together, A² and D¹ together, R^(1A), R², R^(2A),R³, R^(3A), R⁴, R^(4A), R⁶, R⁶C, R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A),R¹³, R^(13A), R¹⁴, R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹, R^(19A),R²⁰, R^(20A), R²³, R^(23A), R²⁴, R^(24A), R²⁵, R^(25A), R²⁶, R^(26A),R²⁷, R^(27A), R²⁸, R^(28A), R²⁹, R^(29A), R³⁰, R^(30A), R^(37B), R³⁸,R^(38A), R³⁹, R^(39A), R⁴⁰, and R^(40A) are independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷,NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷,NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂,NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R¹⁷, SO₂NH₂, SO₂NHR¹⁷,SO₂N(R¹⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R¹⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with R^(58A); R^(58A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with R^(59A); R^(59A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(60A); R^(60A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶²,NH₂, NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NHR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with R^(63A); R^(63A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with R^(64A); R^(64A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with R^(65A);R^(65A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³,R⁶⁴, R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two orthree or four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸,SO₂R⁶⁸, C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂,NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸,NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸,NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸,C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with R^(69A); R^(69A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with R^(70A); R^(70A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(71A); R^(71A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁷³,OR⁷³, SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³,NH₂, NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁷³ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstitutedor substituted with one or two or three or four of independentlyselected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH,C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI.

Another embodiment of this invention pertains to compounds of Formula(I), wherein

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

G¹ is H, or C(O)OR;

R is alkyl;

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with R^(2A); R^(2A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with R^(3A); R^(3A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(4A); R^(4A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR⁷, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with R^(8A); R^(8A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with R^(9A); R^(9A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(10A); R^(10A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R¹²,OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹²,NH₂, NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with R^(13A); R^(13A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with R^(14A); R^(14A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with R^(15A); R^(15A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with R^(18A); R^(18A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with R^(19A); R^(19A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with R^(20A); R^(20A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²)₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²,SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl, which is unfused or fused with R^(23A); R^(23A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with R^(24A); R^(24A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(25A); R^(25A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with R^(26A); R^(26A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with R^(27A); R^(27A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with R^(28A); R^(28A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with R^(29A); R^(29A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁰ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with R^(30A);R^(30A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B)SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B) NR^(37B)C(O)R^(37B) NHS(O)₂R^(37B)NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B) NR^(37B)C(O)OR^(37B) NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B)NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B) C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B) C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, or R^(37C);

R^(37C) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with R^(38A); R^(38A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with R^(39A); R^(39A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(40A); R^(40A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are substituted (i.e.,if Z^(1A) and Z^(2A) are absent) or further substituted (i.e., if Z^(1A)and Z^(2A) are present) with R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹,CO(O)R⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹,NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹, NHC(O)NHR⁴¹,NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂,C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹, C(O)NR⁴¹SO₂R⁴¹, SO₂NHR⁴¹, SO₂N(R⁴¹)₂,C(N)NHR⁴¹, or C(N)N(R⁴¹)₂;

R⁴¹ is heteroaryl, which is fused with R^(43A); R^(43A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; which is unfused;

wherein the cyclic moieties represented by E¹ and Y¹ together, Y¹ and B¹together, A² and B¹ together, A² and D¹ together, R^(1A), R², R^(2A),R³, R^(3A), R⁴, R^(4A), R⁶, R⁶C, R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A),R¹³, R^(13A), R¹⁴, R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹, R^(19A),R²⁰, R^(20A), R²³, R^(23A), R²⁴, R^(24A), R²⁵, R^(25A), R²⁶, R^(26A),R²⁷, R^(27A), R²⁸, R^(28A), R²⁹, R^(29A), R³⁰, R^(30A), R^(37B), R³⁸,R^(38A), R³⁹, R^(39A), R⁴⁰, and R^(40A) are independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷,NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷,NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂,NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷,SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with R^(58A); R^(58A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with R^(59A); R^(59A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(60A); R^(60A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶²,NH₂, NR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with R^(63A); R^(63A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with R^(64A); R^(64A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(65A); R^(65A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³,R⁶⁴, R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two orthree or four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸,SO₂R⁶⁸, C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂,NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸,NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸,NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸,C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with R^(69A); R^(69A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with R^(70A); R^(70A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(71A); R^(71A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁷³,OR⁷³, SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³,NH₂, NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁷³ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstitutedor substituted with one or two or three or four of independentlyselected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH,C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI.

Another embodiment of this invention pertains to compounds of Formula(I), wherein

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, SO₂R¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or

E¹ and Y¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², B¹, and D¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

A², D¹, and E¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and B¹, together with the atoms to which they are attached, arebenzene, naphthylene, heteroarene cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

D¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); or

A² and D¹, together with the atoms to which they are attached, arebenzene, naphthalene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; and

B¹, E¹, and Y¹ are independently selected H, R¹, OR¹, SR¹, S(O)R¹,SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂,NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂,C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃,OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A);

G¹ is H, or C(O)OR;

R is alkyl;

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is cycloalkyl, cycloalkenyl or cycloalkynyl;

R² is phenyl, which is unfused or fused with R^(2A); R^(2A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl, which is unfused or fused with R^(3A); R^(3A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(4A); R^(4A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶,NC(R^(6A))(R⁶B), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NR⁷C(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷,SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR⁷, OH, (O),C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl, which is unfused or fused with R^(8A); R^(8A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl, which is unfused or fused with R^(9A); R^(9A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(10A); R^(10A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R¹²,OR¹², SR¹², S(O)R¹², SO₂R¹², C(O)R¹², CO(O)R¹², OC(O)R¹², OC(O)OR¹²,NH₂, NHR¹², N(R¹²)₂, NHC(O)R¹², NR¹²C(O)R¹², NHS(O)₂R¹², NR¹²S(O)₂R¹²,NHC(O)OR¹², NR¹²C(O)OR¹², NHC(O)NH₂, NHC(O)NHR¹², NHC(O)N(R¹²)₂,NR¹²C(O)NHR¹², NR¹²C(O)N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂,C(O)NHOH, C(O)NHOR¹², C(O)NHSO₂R¹², C(O)NR¹²SO₂R¹², SO₂NH₂, SO₂NHR¹²,SO₂N(R¹²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR¹², C(N)N(R¹²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl, which is unfused or fused with R^(13A); R^(13A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, which is unfused or fused with R^(14A); R^(14A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with R^(15A); R^(15A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl, which is unfused or fused with R^(18A); R^(18A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl, which is unfused or fused with R^(19A); R^(19A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with R^(20A); R^(20A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R²²,OR²², SR²², S(O)R²², SO₂R²², C(O)R²², CO(O)R²², OC(O)R²², OC(O)OR²²,NH₂, NHR²², N(R²²)₂, NHC(O)R²², NR²²C(O)R²², NHS(O)₂R²², NR²²S(O)₂R²²,NHC(O)OR²², NR²²C(O)OR²², NHC(O)NH₂, NHC(O)NHR²², NHC(O)N(R²²)₂,NR²²C(O)NHR²², NR²²C(O)N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂,C(O)NHOH, C(O)NHOR²², C(O)NHSO₂R²², C(O)NR²²SO₂R²², SO₂NH₂, SO₂NHR²²,SO₂N(R²²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR²², C(N)N(R²²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl, which is unfused or fused with R^(23A); R^(23A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene, which is unfused or fused with R^(24A); R^(24A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(25A); R^(25A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

Z¹ is R²⁶ or R²⁷;

Z² is R²⁸, R²⁹ or R³⁰;

Z^(1A) and Z^(2A) are both absent or are taken together to form CH₂,CH₂CH₂ or Z^(12A);

Z^(12A) is C₂-C₆-alkylene having one or two CH₂ moieties replaced by NH,N(CH₃), S, S(O) or SO₂;

L¹ is a R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, C(O)R³⁷, CO(O)R³⁷, OC(O)R³⁷,OC(O)OR³⁷, NHR³⁷, C(O)NH, C(O)NR³⁷, C(O)NHOR³⁷, C(O)NHSO₂R³⁷, SO₂NH,SO₂NHR³⁷, C(N)NH, C(N)NHR³⁷;

R²⁶ is phenylene, which is unfused or fused with R^(26A); R^(26A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁷ is heteroarylene, which is unfused or fused with R^(27A); R^(27A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁸ is phenylene, which is unfused or fused with R^(28A); R^(28A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroarylene, which is unfused or fused with R^(29A); R^(29A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³¹ is cycloalkylene, cycloalkenylene, heterocycloalkylene orheterocycloalkenylene, each of which is unfused or fused with R^(30A);R^(30A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁷ is a bond or R^(37A);

R^(37A) is alkylene, alkenylene, or alkynylene, each of which isunsubstituted or substituted with one or two or three independentlyselected R^(37B), OR^(37B), SR^(37B), S(O)R^(37B)SO₂R^(37B),C(O)R^(37B), CO(O)R^(37B), OC(O)R^(37B), OC(O)OR^(37B), NH₂, NHR^(37B),N(R^(37B))₂, NHC(O)R^(37B) NR^(37B)C(O)R^(37B) NHS(O)₂R^(37B)NR^(37B)S(O)₂R^(37B), NHC(O)OR^(37B) NR^(37B)C(O)OR^(37B) NHC(O)NH₂,NHC(O)NHR^(37B), NHC(O)N(R^(37B))₂, NR^(37B)C(O)NHR^(37B)NR^(37B)C(O)N(R^(37B))₂, C(O)NH₂, C(O)NHR^(37B) C(O)N(R^(37B))₂,C(O)NHOH, C(O)NHOR^(37B) C(O)NHSO₂R^(37B), C(O)NR^(37B)SO₂R^(37B),SO₂NH₂, SO₂NHR^(37B), SO₂N(R^(37B))₂, C(O)H, C(O)OH, C(N)NH₂,C(N)NHR^(37B), C(N)N(R^(37B))₂, CNOH, CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br and I substituents;

R^(37B) is alkyl, alkenyl, alkynyl, or R^(37C);

R^(37C) is phenyl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl;

Z³ is R³⁸, R³⁹ or R⁴⁰;

R³⁸ is phenyl, which is unfused or fused with R^(38A); R^(38A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl, which is unfused or fused with R^(39A); R^(39A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(40A); R^(40A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are substituted (i.e.,if Z^(1A) and Z^(2A) are absent) or further substituted (i.e., if Z^(1A)and Z^(2A) are present) with R⁴¹, OR⁴¹, SR⁴¹, S(O)R⁴¹, SO₂R⁴¹, C(O)R⁴¹,CO(O)R⁴¹, OC(O)R⁴¹, OC(O)OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)R⁴¹, NR⁴¹C(O)R⁴¹,NHS(O)₂R⁴¹, NR⁴¹S(O)₂R⁴¹, NHC(O)OR⁴¹, NR⁴¹C(O)OR⁴¹, NHC(O)NHR⁴¹,NHC(O)N(R⁴¹)₂, NR⁴¹C(O)NHR⁴¹, NR⁴¹C(O)N(R⁴¹)₂, C(O)NHR⁴¹, C(O)N(R⁴¹)₂,C(O)NHOR⁴¹, C(O)NHSO₂R⁴¹, C(O)NR⁴¹SO₂R⁴¹, SO₂NHR⁴¹, SO₂N(R⁴¹)₂,C(N)NHR⁴¹, or C(N)N(R⁴¹)₂;

R⁴¹ is heteroaryl, which is fused with R^(43A); R^(43A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; which is fused with benzene, heteroarene or R^(43B);R^(43B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

wherein the cyclic moieties represented by E¹ and Y¹ together, Y¹ and B¹together, A² and B¹ together, A² and D¹ together, R^(1A), R², R^(2A),R³, R^(3A), R⁴, R^(4A), R⁶, R⁶C, R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A),R¹³, R^(13A), R¹⁴, R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹, R^(19A),R²⁰, R^(20A), R²³, R^(23A), R²⁴, R^(24A), R²⁵, R^(25A), R²⁶, R^(26A),R²⁷, R^(27A), R²⁸, R^(28A), R²⁹, R^(29A), R³⁰, R^(30A), R^(37B), R³⁸,R^(38A), R³⁹, R^(39A), R⁴⁰, and R^(40A) are independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five of independently selected R^(57A), R⁵⁷,OR⁵⁷, SR⁵⁷, S(O)R⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, OC(O)R⁵⁷, OC(O)OR⁵⁷,NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷, NR⁵⁷C(O)R⁵⁷, NHS(O)₂R⁵⁷, NR⁵⁷S(O)₂R⁵⁷,NHC(O)OR⁵⁷, NR⁵⁷C(O)OR⁵⁷, NHC(O)NH₂, NHC(O)NHR⁵⁷, NHC(O)N(R⁵⁷)₂,NR⁵⁷C(O)NHR⁵⁷, NR⁵⁷C(O)N(R⁵⁷)₂, C(O)NH₂, C(O)NHR⁵⁷, C(O)N(R⁵⁷)₂,C(O)NHOH, C(O)NHOR⁵⁷, C(O)NHSO₂R⁵⁷, C(O)NR⁵⁷SO₂R⁵⁷, SO₂NH₂, SO₂NHR⁵⁷,SO₂N(R⁵⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁷, C(N)N(R⁵⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl, which is unfused or fused with R^(58A); R^(58A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁹ is heteroaryl, which is unfused or fused with R^(59A); R^(59A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(60A); R^(60A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶²,OR⁶², SR⁶², S(O)R⁶², SO₂R⁶², C(O)R⁶², CO(O)R⁶², OC(O)R⁶², OC(O)OR⁶²,NH₂, NHR⁶², N(R⁶²)₂, NHC(O)R⁶², NR⁶²C(O)R⁶², NHS(O)₂R⁶², NR⁶²S(O)₂R⁶²,NHC(O)OR⁶², NR⁶²C(O)OR⁶², NHC(O)NH₂, NHC(O)NHR⁶², NHC(O)N(R⁶²)₂,NR⁶²C(O)NHR⁶², NR⁶²C(O)N(R⁶²)₂, C(O)NH₂, C(O)NHR⁶², C(O)N(R⁶²)₂,C(O)NHOH, C(O)NHOR⁶², C(O)NHSO₂R⁶², C(O)NR⁶²SO₂R⁶², SO₂NH₂, SO₂NR⁶²,SO₂N(R⁶²)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶², C(N)N(R⁶²)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁶² is R⁶³, R⁶⁴, R⁶⁵ or R⁶⁶;

R⁶³ is phenyl, which is unfused or fused with R^(63A); R^(63A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁴ is heteroaryl, which is unfused or fused with R^(64A); R^(64A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶⁵ is cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, each of which is unfused or fused with R^(65A);R^(65A) is benzene, heteroarene, cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁶⁶ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁶⁷,OR⁶⁷, SR⁶⁷, S(O)R⁶⁷, SO₂R⁶⁷, C(O)R⁶⁷, CO(O)R⁶⁷, OC(O)R⁶⁷, OC(O)OR⁶⁷,NH₂, NHR⁶⁷, N(R⁶⁷)₂, NHC(O)R⁶⁷, NR⁶⁷C(O)R⁶⁷, NHS(O)₂R⁶⁷, NR⁶⁷S(O)₂R⁶⁷,NHC(O)OR⁶⁷, NR⁶⁷C(O)OR⁶⁷, NHC(O)NH₂, NHC(O)NHR⁶⁷, NHC(O)N(R⁶⁷)₂,NR⁶⁷C(O)NHR⁶⁷, NR⁶⁷C(O)N(R⁶⁷)₂, C(O)NH₂, C(O)NHR⁶⁷, C(O)N(R⁶⁷)₂,C(O)NHOH, C(O)NHOR⁶⁷, C(O)NHSO₂R⁶⁷, C(O)NR⁶⁷SO₂R⁶⁷, SO₂NH₂, SO₂NR⁶⁷,SO₂N(R⁶⁷)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁶⁷, C(N)N(R⁶⁷)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁶⁷ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, R⁵⁹, R⁶⁰, R⁶³,R⁶⁴, R⁶⁵, and R⁶⁷ are unsubstituted or substituted with one or two orthree or four of independently selected R⁶⁸, OR⁶⁸, SR⁶⁸, S(O)R⁶⁸,SO₂R⁶⁸, C(O)R⁶⁸, CO(O)R⁶⁸, OC(O)R⁶⁸, OC(O)OR⁶⁸, NH₂, NHR⁶⁸, N(R⁶⁸)₂,NHC(O)R⁶⁸, NR⁶⁸C(O)R⁶⁸, NHS(O)₂R⁶⁸, NR⁶⁸S(O)₂R⁶⁸, NHC(O)OR⁶⁸,NR⁶⁸C(O)OR⁶⁸, NHC(O)NH₂, NHC(O)NHR⁶⁸, NHC(O)N(R⁶⁸)₂, NR⁶⁸C(O)NHR⁶⁸,NR⁶⁸C(O)N(R⁶⁸)₂, C(O)NH₂, C(O)NHR⁶⁸, C(O)N(R⁶⁸)₂, C(O)NHOH, C(O)NHOR⁶⁸,C(O)NHSO₂R⁶⁸, C(O)NR⁶⁸SO₂R⁶⁸, SO₂NH₂, SO₂NHR⁶⁸, SO₂N(R⁶⁸)₂, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁶⁸, C(N)N(R⁶⁸)₂, CNOH, CNOCH₃, OH, (O), CN, N₃,NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I;

R⁶⁸ is R⁶⁹, R⁷⁰, R⁷¹ or R⁷²;

R⁶⁹ is phenyl, which is unfused or fused with R^(69A); R^(69A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷⁰ is heteroaryl, which is unfused or fused with R^(70A); R^(70A) isbenzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷¹ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with R^(71A); R^(71A) is benzene,heteroarene, cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁷² is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁷³,OR⁷³, SR⁷³, S(O)R⁷³, SO₂R⁷³, C(O)R⁷³, CO(O)R⁷³, OC(O)R⁷³, OC(O)OR⁷³,NH₂, NHR⁷³, N(R⁷³)₂, NHC(O)R⁷³, NR⁷³C(O)R⁷³, NHS(O)₂R⁷³, NR⁷³S(O)₂R⁷³,NHC(O)OR⁷³, NR⁷³C(O)OR⁷³, NHC(O)NH₂, NHC(O)NHR⁷³, NHC(O)N(R⁷³)₂,NR⁷³C(O)NHR⁷³, NR⁷³C(O)N(R⁷³)₂, C(O)NH₂, C(O)NHR⁷³, C(O)N(R⁷³)₂,C(O)NHOH, C(O)NHOR⁷³, C(O)NHSO₂R⁷³, C(O)NR⁷³SO₂R⁷³, SO₂NH₂, SO₂NHR⁷³,SO₂N(R⁷³)₂, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁷³, C(N)N(R⁷³)₂, CNOH,CNOCH₃, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI;

R⁷³ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and

wherein the moieties represented by R⁶⁹, R⁷⁰, and R⁷¹ are unsubstitutedor substituted with one or two or three or four of independentlyselected NH₂, C(O)NH₂, C(O)NHOH, SO₂NH₂, CF₃, CF₂CF₃, C(O)H, C(O)OH,C(N)NH₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br orI.

In one embodiment of Formula (I), A¹ is N, and G¹ is H. In anotherembodiment of Formula (I), A¹ is C(A²) and G¹ is H. In anotherembodiment of Formula (I), A¹ is C(A²); A² is H, F, Cl, Br, or I; and G¹is H. In another embodiment of Formula (I), A¹ is C(A²); A² is H; and G¹is H.

In one embodiment of Formula (I), B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Cl,Br, or I. In another embodiment of Formula (I), A¹ is C(A²); A² is H; B¹is NHR¹, and G¹ is H. In another embodiment of Formula (I), A¹ is C(A²);A² is H; B¹ is OR¹, and G¹ is H. In another embodiment of Formula (I),A¹ is C(A²); A² is H; B¹ is Cl; and G¹ is H. In another embodiment ofFormula (I), A¹ is C(A²); A² is H; B¹ is R¹; and G¹ is H. In anotherembodiment of Formula (I), A¹ is N; B¹ is NHR¹; and G¹ is H. In anotherembodiment of Formula (I), A¹ is N; B¹ is OR¹; and G¹ is H. In anotherembodiment of Formula (I), A¹ is N; B¹ is Cl; and G¹ is H. In anotherembodiment of Formula (I), A¹ is N; B¹ is R¹; and G¹ is H.

In one embodiment of Formula (I), D¹ is H or Cl. In another embodimentof Formula (I), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and G¹ is H.In another embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is Cl; and G¹ is H. In another embodiment of Formula (I), A¹ isC(A²); A² is H; B¹ is OR¹; D¹ is H; and G¹ is H. In another embodimentof Formula (I), A¹ is C(A²); A² is H; B¹ is Cl; D¹ is H; and G¹ is H. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is R¹; D¹ isH; and G¹ is H. In another embodiment of Formula (I), A¹ is N; B¹ isNHR¹; D¹ is H; and G¹ is H. In another embodiment of Formula (I), A¹ isN; B¹ is NHR¹; D¹ is Cl; and G¹ is H. In another embodiment of Formula(I), A¹ is N; B¹ is OR¹; D¹ is H; and G¹ is H. In another embodiment ofFormula (I), A¹ is N; B¹ is Cl; D¹ is H; and G¹ is H. In anotherembodiment of Formula (I), A¹ is N; B¹ is R¹; D¹ is H; and G¹ is H.

In one embodiment of Formula (I), E¹ is H. In another embodiment ofFormula (I), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and G¹is H. In another embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ isNHR¹; E¹ is H; D¹ is Cl; and G¹ is H. In another embodiment of Formula(I), A¹ is C(A²); A² is H; B¹ is OR¹; D¹ is H; E¹ is H; and G¹ is H. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is Cl; D¹ isH; E¹ is H; and G¹ is H. In another embodiment of Formula (I), A¹ isC(A²); A² is H; B¹ is R¹; D¹ is H; E¹ is H; and G¹ is H. In anotherembodiment of Formula (I), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; and G¹is H. In another embodiment of Formula (I), A¹ is N; B¹ is NHR¹; E¹ isH; D¹ is Cl, and G¹ is H. In another embodiment of Formula (I), A¹ is N;B¹ is OR¹; D¹ is H; E¹ is H; and G¹ is H. In another embodiment ofFormula (I), A¹ is N; B¹ is Cl; D¹ is H; E¹ is H; and G¹ is H. Inanother embodiment of Formula (I), A¹ is N; B¹ is R¹; D¹ is H; E¹ is H;and G¹ is H.

In one embodiment of Formula (I), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, or C(O)NH₂. In another embodiment of Formula(I), Y¹ is H. In another embodiment of Formula (I), Y¹ is CN. In anotherembodiment of Formula (I), Y¹ is F, Cl, Br, or I. In another embodimentof Formula (I), Y¹ is CF₃. In another embodiment of Formula (I), Y¹ isSR¹⁷. In another embodiment of Formula (I), Y¹ is OR¹⁷. In anotherembodiment of Formula (I), Y¹ is NO₂. In another embodiment of Formula(I), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (I), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (I), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. Inanother embodiment of Formula (I), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹is H; E¹ is H; G¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl oralkynyl. In another embodiment of Formula (I), A¹ is C(A²); A² is H; B¹is NHR¹; D¹ is H; E¹ is H; G¹ is H; and Y¹ is NO₂. In another embodimentof Formula (I), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; G¹is H; and Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl substituted with three F.In another embodiment of Formula (I), A¹ is N; B¹ is NHR¹; D¹ is H; E¹is H; G¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl.In another embodiment of Formula (I), A¹ is N; B¹ is NHR¹; D¹ is H; E¹is H; G¹ is H; and Y¹ is NO₂. In another embodiment of Formula (I), A¹is N; B¹ is NHR¹; D¹ is H; E¹ is H; G¹ is H; and Y¹ is SO₂R¹⁷; whereinR¹⁷ is alkyl substituted with three F.

In one embodiment of Formula (I), G¹ is H; A¹ is N or C(A²); and A² isH. In another embodiment of Formula (I), G¹ is H; A¹ is N or C(A²); A²is H; and B¹ is NHR¹. In another embodiment of Formula (I), G¹ is H; A¹is N or C(A²); A² is H; B¹ is NHR¹; and D¹ is H. In another embodimentof Formula (I), G¹ is H; A¹ is N or C(A²); A² is H; B¹ is NHR¹; D¹ is H;and E¹ is H. In another embodiment of Formula (I), G¹ is H; A¹ is N orC(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂.

In one embodiment of Formula (I), Y¹ and B¹, together with the atoms towhich they are attached, are benzene. In another embodiment of Formula(I), Y¹ and B¹, together with the atoms to which they are attached, areheteroarene. In another embodiment of Formula (I), A¹ is C(A²); A², G¹,E¹, and D¹ are independently selected H; and Y¹ and B¹, together withthe atoms to which they are attached, are benzene. In another embodimentof Formula (I), A¹ is C(A²); A², G¹, E¹, and D¹ are independentlyselected H; and Y¹ and B¹, together with the atoms to which they areattached, are heteroarene.

In one embodiment of Formula (I), R¹ is R⁴ or R⁵. In one embodiment ofFormula (I), R¹ is R⁴. In one embodiment of Formula (I), R¹ is R⁵. Inone embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl. In one embodimentof Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl or heterocycloalkyl. Inone embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl. In oneembodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷ or N(R⁵⁷)₂. In another embodiment ofFormula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ringis cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷;and R⁵⁷ is R⁶⁰. In another embodiment of Formula (I), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (I), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl. Inanother embodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂. In another embodiment of Formula (I), R¹ isR⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; andwherein the cyclohexyl ring is substituted with N(R⁵⁷)₂; R⁵⁷ is R⁶¹; andR⁶¹ is alkyl which is unsubstituted or substituted with R⁶². In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkyl which isunsubstituted or substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ iscycloalkyl. In another embodiment of Formula (I), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkylwhich is substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ is cyclopropyl.

In one embodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is substituted as defined herein. In anotherembodiment of Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is substituted with R⁵⁷. In another embodimentof Formula (I), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein theheterocycloalkyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰ or R⁶¹. Inanother embodiment of Formula (I), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperdinyl or piperizinyl; andwherein the piperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷is R⁶⁰ or R⁶¹; R⁶⁰ is heterocycloalkyl; and R⁶¹ is alkyl. In anotherembodiment of Formula (I), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein thepiperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰is heterocycloalkyl; wherein the heterocycloalkyl is tetrahydropyranyl.In another embodiment of Formula (I), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperdinyl or piperizinyl; andwherein the piperdinyl or piperizinyl ring is substituted with R⁵⁷; R¹⁷is R⁶¹; R⁶¹ is alkyl; and the alkyl is methyl. In another embodiment ofFormula (I), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein thepiperdinyl or piperizinyl ring is substituted with C(O)OR⁵⁷; R⁵⁷ is R⁶¹;R⁶¹ is alkyl; and the alkyl is methyl.

In one embodiment of Formula (I), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (I), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,OH, CN, or F. In another embodiment of Formula (I), R¹ is R⁵; and R⁵ isalkyl which is substituted with R⁷, OR⁷, NHR⁷, or N(R⁷)₂.

In one embodiment of Formula (I), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (I), R⁷ is R⁸ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (I), R⁷ is R⁹ which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (I), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (I), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodiment of Formula (I), R⁸ is phenyl which is unsubstituted orsubstituted as defined herein.

In one embodiment of Formula (I), R⁹ is heteroaryl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (I), R⁹ is furanyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (I), R⁹ is furanyl;which is unsubstituted.

In one embodiment of Formula (I), R¹⁰ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, heterocycloalkyl which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (I), R¹⁰ is heterocycloalkyl which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (I), R¹⁰is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,oxetanyl, piperdinyl, or pyrrolidinyl, which are unsubstituted orsubstituted as defined herein. In another embodiment of Formula (I), R¹⁰is tetrahydropyranyl; which is unsubstituted or substituted as definedherein. In another embodiment of Formula (I), R¹⁰ is morpholinyl; whichis unsubstituted or substituted as defined herein. In another embodimentof Formula (I), R¹⁰ is cycloalkyl which is unsubstituted or substitutedas defined herein. In another embodiment of Formula (I), R¹⁰ iscycloalkyl which is unsubstituted or substituted as defined herein. Inanother embodiment of Formula (I), R¹⁰ is cyclohexyl, cyclopropyl,cyclobutyl, or bicyclo[2.2.1]heptanyl, which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (I), R¹⁰is heterocycloalkyl which is fused with R^(10A); and R^(10A) isheteroarene. In another embodiment of Formula (I), R¹⁰ is5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl.

In one embodiment of Formula (I), R¹¹ is alkyl, alkenyl or alkynyl whichare unsubstituted or substituted as defined herein. In anotherembodiment of Formula (I), R¹¹ is alkyl. In another embodiment ofFormula (I), R¹¹ is methyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (I), R¹¹ is alkyl;which is substituted as defined herein. In another embodiment of Formula(I), R¹¹ is alkyl; which is substituted with R¹², OR¹², or CF₃. Inanother embodiment of Formula (I), R¹¹ is alkyl; which is substitutedwith OR¹², R¹² is R¹⁶; and R¹⁶ is alkyl. In another embodiment ofFormula (I), R¹¹ is alkyl; which is substituted with CF₃. In anotherembodiment of Formula (I), R¹¹ is alkyl; which is substituted with R¹²;R¹² is R¹⁴; and R¹⁴ is heteroaryl.

In one embodiment of Formula (I), A¹ is N or C(A²);

A² is H, F, Br, I, or Cl;

B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Br, I or Cl;

D¹ is H, F, Br, I, or Cl;

E¹ is H; and

Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃, R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, orC(O)NH₂; or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, heteroarene, or heterocycloalkene; and

A², D¹, and E¹ are independently selected H;

G¹ is H, or C(O)OR;

R is alkyl;

R¹ is R⁴ or R⁵;

R⁴ is cycloalkyl, or heterocycloalkyl;

R⁵ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R⁷, OR⁷, NHR⁷,N(R⁷)₂, CN, OH, F, Cl, Br or I;

R⁷ is R⁸, R⁹, R¹⁰, or R¹¹;

R⁸ is phenyl;

R⁹ is heteroaryl;

R¹⁰ is cycloalkyl, cycloalkenyl, or heterocycloalkyl; each of which isunfused or fused with R^(10A), R^(10A) is heteroarene;

R¹¹ is alkyl each of which is unsubstituted or substituted with one ortwo or three of independently selected R¹², OR¹² or CF₃;

R¹² is R¹⁴ or R¹⁶;

R¹⁴ is heteroaryl;

R¹⁶ is alkyl;

R¹⁷ is R²¹;

R²¹ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R²², F, Cl, Br or I;

R²² is R²⁵;

R²⁵ is heterocycloalkyl;

Z¹ is R²⁶;

Z² is R³⁰;

Z^(1A) and Z^(2A) are both absent;

L¹ is a R³⁷;

R²⁶ is phenylene;

R³⁰ is heterocycloalkylene;

R³⁷ is R^(37A);

R^(37A) is alkylene;

Z³ is R³⁸, or R⁴⁰;

R³⁸ is phenyl;

R⁴⁰ is cycloalkyl, cycloalkenyl, or heterocycloalkenyl;

wherein the moiety represented by R²⁶ is substituted with OR⁴¹;

R⁴¹ is heteroaryl, which is fused with R^(43A); R^(43A) is heteroarene;which is unfused or fused with benzene;

wherein the cyclic moieties represented by Y¹ and B¹ together, R⁴, R⁸,R¹⁰, R²⁵, R³⁰, R³⁸, and R⁴⁰ are independently unsubstituted, furtherunsubstituted, substituted or further substituted with one or two orthree or four or five of independently selected R^(57A), R⁵⁷, OR⁵⁷,SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, C(O)N(R⁵⁷)₂, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷,NHS(O)₂R⁵⁷, OH, CN, (O), F, Cl, Br or I;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁵⁹, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl;

R⁵⁹ is heteroaryl;

R⁶⁰ is cycloalkyl, or heterocycloalkyl;

R⁶¹ is alkyl which is unsubstituted or substituted with one or two orthree of independently selected R⁶², OR⁶², N(R⁶²)₂, C(O)OH, CN, F, Cl,Br or I;

R⁶² is R⁶⁵, or R⁶⁶;

R⁶⁵ is cycloalkyl, or heterocycloalkyl;

R⁶⁶ is alkyl which is unsubstituted or substituted with OR⁶⁷;

R⁶⁷ is alkyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, and R⁶⁰ areunsubstituted or substituted with one or two or three or four ofindependently selected R⁶⁸, F, Cl, Br or I;

R⁶⁸ is R⁷¹ or R⁷²;

R⁷¹ is heterocycloalkyl; and

R⁷² is alkyl, which is unsubstituted or substituted with one or two F.

Still another embodiment pertains to compounds having Formula (I), whichare

-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(2-naphthylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   5-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethoxy)nicotinamide;-   N-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-bromo-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-oxo-3,4-dihydroquinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-3-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   and therapeutically acceptable salts, and metabolites thereof.-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yl    oxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S,3R)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,3S)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[cis-3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide;-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[trans-4-(fluoromethyl)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclobutylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-2-oxopiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylazetidin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-cyclopropylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclobutylmorpholin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydrofuran-3-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(trifluoromethoxy)benzyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxaspiro[4.5]dec-8-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[cis-3-morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-fluoro-1-(methylsulfonyl)piperidin-4-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[3-(dimethylamino)propoxy]benzyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(E)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(Z)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dien-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   (2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholin-4-yl)acetic    acid;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   ethyl    4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)piperazine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(2-methoxyethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]piperazine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-(pentafluoro-λ⁶-sulfanyl)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(oxetan-3-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3R)-tetrahydrofuran-3-ylamino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(oxetan-3-yl)azetidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl}sulfonyl)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(3-furylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-chloro-6-[2-(tetrahydrofuran-2-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-methylpiperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(cyclopropylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-chloro-6-(2-methoxyethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(methoxyacetyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide;-   N-({5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(trans-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(cis-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(1,3-thiazol-5-ylmethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-chloro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl)phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,5-difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,4-difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-{[3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   methyl    2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholine-4-carboxylate;-   2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}phenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   (2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   N-[(5-chloro-6-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2,2-difluorocyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(2-oxaspiro[3.5]non-7-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-cyano-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2-oxaspiro[3.5]non-7-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   {[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methyl    pivalate;-   {[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methyl    butyrate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-cyano-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)morpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methoxymethyl)cyclohexyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-chloro-6-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;    and therapeutically acceptable salts, and metabolites thereof.

Still another embodiment pertains to4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;and therapeutically acceptable salts, and metabolites thereof.

Still another embodiment pertains toTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;and therapeutically acceptable salts, and metabolites thereof.

Still another embodiment pertains toCis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;and therapeutically acceptable salts, and metabolites thereof.

Still another embodiment pertains toTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;and therapeutically acceptable salts, and metabolites thereof.

Still another embodiment pertains to4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;and therapeutically acceptable salts, and metabolites thereof.

Another embodiment pertains to the compoundN-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(²H₈)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compoundN-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which areN-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which are4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;

-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;    or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compoundN-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Still another embodiment pertains to compounds having Formula (I) orFormula (II), which areN-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;or a pharmaceutically acceptable salt thereof.

Another embodiment pertains to the compound4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideor a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides compounds of Formula(II)

and therapeutically acceptable salts, and metabolites thereof,wherein A¹, B¹, D¹, E¹, Y¹, Z², L¹, and Z³ are as described herein forFormula (II); n is 0, 1, 2, or 3; describing the number of substituentson Z¹; and R¹⁰⁰ is as described for substituents on R²⁶.

In one embodiment of Formula (II), n is 0 or 1. In another embodiment ofFormula (II), n is 0.

In one embodiment of Formula (II), A¹ is N. In another embodiment ofFormula (II), A¹ is C(A²). In another embodiment of Formula (II), A¹ isC(A²); and A² is H, F, Cl, Br, or I. In another embodiment of Formula(II), A¹ is C(A²); and A² is H.

In one embodiment of Formula (II), B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Cl,Br, or I. In another embodiment of Formula (II), A¹ is C(A²); A² is H;and B¹ is NHR¹. In another embodiment of Formula (II), A¹ is C(A²); A²is H; and B¹ is OR¹. In another embodiment of Formula (II), A¹ is C(A²);A² is H; and B¹ is Cl. In another embodiment of Formula (II), A¹ isC(A²); A² is H; and B¹ is RU. In another embodiment of Formula (II), A¹is N; and B¹ is NHR¹. In another embodiment of Formula (II), A¹ is N;and B¹ is OR¹. In another embodiment of Formula (II), A¹ is N; and B¹ isCl. In another embodiment of Formula (II), A¹ is N; and B¹ is R¹.

In one embodiment of Formula (II), D¹ is H or Cl. In another embodimentof Formula (II), A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H. Inanother embodiment of Formula (II), A¹ is C(A²); A² is H; B¹ is NHR¹;and D¹ is Cl. In another embodiment of Formula (II), A¹ is C(A²); A² isH; B¹ is OR¹; and D¹ is H. In another embodiment of Formula (II), A¹ isC(A²); A² is H; B¹ is Cl; and D¹ is H. In another embodiment of Formula(II), A¹ is C(A²); A² is H; B¹ is R¹; and D¹ is H. In another embodimentof Formula (II), A¹ is N; B¹ is NHR¹; and D¹ is H. In another embodimentof Formula (II), A¹ is N; B¹ is NHR¹; and D¹ is Cl. In anotherembodiment of Formula (II), A¹ is N; B¹ is OR¹; and D¹ is H. In anotherembodiment of Formula (II), A¹ is N; B¹ is Cl; and D¹ is H. In anotherembodiment of Formula (II), A¹ is N; B¹ is R¹; and D¹ is H.

In one embodiment of Formula (II), E¹ is H. In another embodiment ofFormula (II), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (II), A¹ is C(A²); A² is H; B¹ is NHR¹; E¹is H; and D¹ is Cl. In another embodiment of Formula (II), A¹ is C(A²);A² is H; B¹ is OR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (II), A¹ is C(A²); A² is H; B¹ is Cl; D¹ is H; and E¹ is H. Inanother embodiment of Formula (II), A¹ is C(A²); A² is H; B¹ is R¹; D¹is H; and E¹ is H. In another embodiment of Formula (II), A¹ is N; B¹ isNHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (II), A¹ isN; B¹ is NHR¹; E¹ is H; and D¹ is Cl. In another embodiment of Formula(II), A¹ is N; B¹ is OR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (II), A¹ is N; B¹ is Cl; D¹ is H; and E¹ is H. In anotherembodiment of Formula (II), A¹ is N; B¹ is R¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (II), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, or C(O)NH₂. In another embodiment of Formula(II), Y¹ is H. In another embodiment of Formula (II), Y¹ is CN. Inanother embodiment of Formula (II), Y¹ is F, Cl, Br, or I. In anotherembodiment of Formula (II), Y¹ is CF₃. In another embodiment of Formula(II), Y¹ is SR¹⁷. In another embodiment of Formula (II), Y¹ is OR¹⁷. Inanother embodiment of Formula (II), Y¹ is NO₂. In another embodiment ofFormula (II), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (II), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (II), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl.In another embodiment of Formula (II), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl oralkynyl. In another embodiment of Formula (II), A¹ is C(A²); A² is H; B¹is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment ofFormula (II), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹is SO₂R¹⁷; wherein R¹⁷ is alkyl substituted with three F. In anotherembodiment of Formula (II), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; andY¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl. In anotherembodiment of Formula (II), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; andY¹ is NO₂. In another embodiment of Formula (II), A¹ is N; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl substitutedwith three F.

In one embodiment of Formula (II), G¹ is H; A¹ is N or C(A²); and A² isH. In another embodiment of Formula (II), G¹ is H; A¹ is N or C(A²); A²is H; and B¹ is NHR¹. In another embodiment of Formula (II), G¹ is H; A¹is N or C(A²); A² is H; B¹ is NHR¹; and D¹ is H. In another embodimentof Formula (II), G¹ is H; A¹ is N or C(A²); A² is H; B¹ is NHR¹; D¹ isH; and E¹ is H. In another embodiment of Formula (II), G¹ is H; A¹ is Nor C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y is NO₂.

In one embodiment of Formula (II), Y¹ and B¹, together with the atoms towhich they are attached, are benzene. In another embodiment of Formula(II), Y¹ and B¹, together with the atoms to which they are attached, areheteroarene. In another embodiment of Formula (II), A¹ is C(A²); A², G¹,E¹, and D¹ are independently selected H; and Y¹ and B¹, together withthe atoms to which they are attached, are benzene. In another embodimentof Formula (II), A¹ is C(A²); A², G¹, E¹, and D¹ are independentlyselected H; and Y¹ and B¹, together with the atoms to which they areattached, are heteroarene.

In one embodiment of Formula (II), R¹ is R⁴ or R⁵. In one embodiment ofFormula (II), R¹ is R⁴. In one embodiment of Formula (II), R¹ is R⁵. Inone embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl. In one embodimentof Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl or heterocycloalkyl. Inone embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl. In oneembodiment of Formula (II), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷ or N(R⁵⁷)₂. In another embodiment ofFormula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (II), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (II), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl. Inanother embodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. In anotherembodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂. In another embodiment of Formula (II), R¹ isR⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; andwherein the cyclohexyl ring is substituted with N(R⁵⁷)₂; R⁵⁷ is R⁶¹; andR⁶¹ is alkyl which is unsubstituted or substituted with R⁶². In anotherembodiment of Formula (II), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkyl which isunsubstituted or substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ iscycloalkyl. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkylwhich is substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ is cyclopropyl

In one embodiment of Formula (II), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (II), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is substituted as defined herein. Inanother embodiment of Formula (II), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is substituted withR⁵⁷. In another embodiment of Formula (II), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperdinyl orpiperizinyl; and wherein the heterocycloalkyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰ or R⁶¹. In another embodiment of Formula (II), R¹ isR⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring ispiperdinyl or piperizinyl; and wherein the piperdinyl or piperizinylring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰ or R⁶¹; R⁶⁰ isheterocycloalkyl; and R⁶¹ is alkyl. In another embodiment of Formula(II), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkylring is piperdinyl or piperizinyl; and wherein the piperdinyl orpiperizinyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl is tetrahydropyranyl. Inanother embodiment of Formula (II), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperdinyl or piperizinyl; andwherein the piperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷is R⁶¹; R⁶¹ is alkyl; and the alkyl is methyl. In another embodiment ofFormula (II), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein thepiperdinyl or piperizinyl ring is substituted with C(O)OR⁵⁷; R⁵⁷ is R⁶¹;R⁶¹ is alkyl; and the alkyl is methyl.

In one embodiment of Formula (II), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (II), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,OH, CN, or F. In another embodiment of Formula (II), R¹ is R⁵; and R⁵ isalkyl which is substituted with R⁷, OR⁷, NHR⁷, or N(R⁷)₂.

In one embodiment of Formula (II), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R⁷ is R⁸ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (II), R⁷ is R⁹ which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (II), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodiment of Formula (II), R⁸ is phenyl which is unsubstitutedor substituted as defined herein.

In one embodiment of Formula (II), R⁹ is heteroaryl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R⁹ is furanyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (II), R⁹ is furanyl;which is unsubstituted.

In one embodiment of Formula (II), R¹⁰ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, heterocycloalkyl which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R¹⁰ is heterocycloalkyl which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (II),R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,oxetanyl, piperdinyl, or pyrrolidinyl, which are unsubstituted orsubstituted as defined herein. In another embodiment of Formula (II),R¹⁰ is tetrahydropyranyl, which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (II), R¹⁰ ismorpholinyl; which is unsubstituted or substituted as defined herein. Inanother embodiment of Formula (II), R¹⁰ is cycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R¹⁰ is cycloalkyl which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (II), R¹⁰ iscyclohexyl, cyclopropyl, cyclobutyl, or bicyclo[2.2.1]heptanyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (II), R¹⁰ is heterocycloalkyl which is fused with R^(10A); andR^(10A) is heteroarene. In another embodiment of Formula (II), R¹⁰ is5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl.

In one embodiment of Formula (II), R¹¹ is alkyl, alkenyl or alkynylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (II), R¹¹ is alkyl. In another embodiment ofFormula (II), R¹¹ is methyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (II), R¹¹ is alkyl;which is substituted as defined herein. In another embodiment of Formula(II), R¹¹ is alkyl; which is substituted with R¹², OR¹², or CF₃. Inanother embodiment of Formula (II), R¹¹ is alkyl; which is substitutedwith OR¹²; R¹² is R¹⁶; and R¹⁶ is alkyl. In another embodiment ofFormula (II), R¹¹ is alkyl; which is substituted with CF₃. In anotherembodiment of Formula (II), R¹¹ is alkyl; which is substituted with R¹²,R¹² is R¹⁴, and R¹⁴ is heteroaryl.

In one embodiment of Formula (II),

n is 0;

A¹ is N or C(A²);

A² is H, F, Br, I, or Cl;

B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Br, I or Cl;

D¹ is H, F, Br, I, or Cl;

E¹ is H; and

Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃, R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, orC(O)NH₂; or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, heteroarene, or heterocycloalkene; and

A², D¹, and E¹ are independently selected H;

R¹ is R⁴ or R⁵;

R⁴ is cycloalkyl, or heterocycloalkyl;

R⁵ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R⁷, OR⁷, NHR⁷,N(R⁷)₂, CN, OH, F, Cl, Br or I;

R⁷ is R⁸, R⁹, R¹⁰, or R¹¹;

R⁸ is phenyl;

R⁹ is heteroaryl;

R¹⁰ is cycloalkyl, cycloalkenyl, or heterocycloalkyl; each of which isunfused or fused with R^(10A), R^(10A) is heteroarene;

R¹¹ is alkyl each of which is unsubstituted or substituted with one ortwo or three of independently selected R¹², OR¹² or CF₃;

R¹² is R¹⁴ or R¹⁶;

R¹⁴ is heteroaryl;

R¹⁶ is alkyl;

R¹⁷ is R²¹;

R²¹ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R²², F, Cl, Br or I;

R²² is R²⁵;

R²⁵ is heterocycloalkyl;

Z² is R³⁰;

Z^(1A) and Z^(2A) are both absent;

L¹ is a R³⁷;

R³⁰ is heterocycloalkylene;

R³⁷ is R^(37A);

R^(37A) is alkylene;

Z³ is R³⁸, or R⁴⁰;

R³⁸ is phenyl;

R⁴⁰ is cycloalkyl, cycloalkenyl, or heterocycloalkenyl;

wherein the cyclic moieties represented by Y¹ and B¹ together, R⁴, R⁸,R¹⁰, R²⁵, R³⁰, R³⁸, and R⁴⁰ are independently unsubstituted, furtherunsubstituted, substituted or further substituted with one or two orthree or four or five of independently selected R^(57A), R⁵⁷, OR⁵⁷,SO₂R⁵⁷, C(O)R⁵⁷, CO(O)R⁵⁷, C(O)N(R⁵⁷)₂, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁵⁷,NHS(O)₂R⁵⁷, OH, CN, (O), F, Cl, Br or I;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl;

R⁶⁰ is cycloalkyl, or heterocycloalkyl;

R⁶¹ is alkyl which is unsubstituted or substituted with one or two orthree of independently selected R⁶², OR⁶², N(R⁶²)₂, C(O)OH, CN, F, Cl,Br or I;

R⁶² is R⁶⁵, or R⁶⁶;

R⁶⁵ is cycloalkyl, or heterocycloalkyl;

R⁶⁶ is alkyl which is unsubstituted or substituted with OR⁶⁷;

R⁶⁷ is alkyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, and R⁶⁰ areunsubstituted or substituted with one or two or three or four ofindependently selected R⁶⁸, F, Cl, Br or I;

R⁶⁸ is R⁷¹ or R⁷²;

R⁷¹ is heterocycloalkyl; and

R⁷² is alkyl, which is unsubstituted or substituted with one or two F.

Still another embodiment pertains to compounds having Formula (II),which are

-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(2-naphthylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   5-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethoxy)nicotinamide;-   N-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-bromo-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-oxo-3,4-dihydroquinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-3-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   and therapeutically acceptable salts, and metabolites thereof.-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yl    oxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S,3R)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,3S)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[cis-3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide;-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[trans-4-(fluoromethyl)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclobutylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-2-oxopiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylazetidin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-cyclopropylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclobutylmorpholin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydrofuran-3-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(trifluoromethoxy)benzyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxaspiro[4.5]dec-8-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[cis-3-morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-fluoro-1-(methylsulfonyl)piperidin-4-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[3-(dimethylamino)propoxy]benzyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(E)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(Z)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dien-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   (2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholin-4-yl)acetic    acid;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   ethyl    4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)piperazine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(2-methoxyethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]piperazine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-(pentafluoro-λ⁶-sulfanyl)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(oxetan-3-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3R)-tetrahydrofuran-3-ylamino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(oxetan-3-yl)azetidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl}sulfonyl)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(3-furylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-chloro-6-[2-(tetrahydrofuran-2-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-methylpiperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(cyclopropylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-chloro-6-(2-methoxyethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(methoxyacetyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide;-   N-({5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(trans-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(cis-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(1,3-thiazol-5-ylmethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-chloro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl)phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,5-difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,4-difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-{[3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   methyl    2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholine-4-carboxylate;-   2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}phenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   (2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   N-[(5-chloro-6-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2,2-difluorocyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(2-oxaspiro[3.5]non-7-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-cyano-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2-oxaspiro[3.5]non-7-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-cyano-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)morpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methoxymethyl)cyclohexyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-chloro-6-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;    and therapeutically acceptable salts, and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(III)

and therapeutically acceptable salts, and metabolites thereof,wherein A¹, B¹, D¹, E¹, and Y¹ are as described herein for Formula (I);R¹⁰⁰ is as described for substituents on R²⁶; n is 0, 1, 2, or 3; R¹ isas described for substituents on R³⁰; p is 0, 1, 2, 3, 4, 5, or 6; R¹⁰²is as described for substituents on R⁴⁰; q is 0, 1, 2, 3, 4, 5, or 6;R¹⁰³ is as described for substituents on R⁵⁸; and r is 0, 1, 2, 3, or 4.

In one embodiment of Formula (III), n, p, r, and q are each 0.

In one embodiment of Formula (III), A¹ is N. In another embodiment ofFormula (III), A¹ is C(A²). In another embodiment of Formula (III), A¹is C(A²); and A² is H, F, Cl, Br, or I. In another embodiment of Formula(III), A¹ is C(A²); and A² is H.

In one embodiment of Formula (III), B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F,Cl, Br, or I. In another embodiment of Formula (III), A¹ is C(A²); A² isH; and B¹ is NHR¹. In another embodiment of Formula (III), A¹ is C(A²);A² is H; and B¹ is OR¹. In another embodiment of Formula (III), A¹ isC(A²); A² is H; and B¹ is Cl. In another embodiment of Formula (III), A¹is C(A²); A² is H; and B¹ is R¹. In another embodiment of Formula (III),A¹ is N; and B¹ is NHR¹. In another embodiment of Formula (III), A¹ isN; and B¹ is OR¹. In another embodiment of Formula (III), A¹ is N; andB¹ is Cl. In another embodiment of Formula (III), A¹ is N; and B¹ is R¹.

In one embodiment of Formula (III), D¹ is H or Cl. In another embodimentof Formula (III), A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H. Inanother embodiment of Formula (III), A¹ is C(A²); A² is H; B¹ is NHR¹;and D¹ is Cl. In another embodiment of Formula (III), A¹ is C(A²); A² isH; B¹ is OR¹; and D¹ is H. In another embodiment of Formula (III), A¹ isC(A²); A² is H; B¹ is Cl; and D¹ is H. In another embodiment of Formula(III), A¹ is C(A²); A² is H; B¹ is R¹; and D¹ is H. In anotherembodiment of Formula (III), A¹ is N; B¹ is NHR¹; and D¹ is H. Inanother embodiment of Formula (III), A¹ is N; B¹ is NHR¹; and D¹ is Cl.In another embodiment of Formula (III), A¹ is N; B¹ is OR¹; and D¹ is H.In another embodiment of Formula (III), A¹ is N; B¹ is Cl; and D¹ is H.In another embodiment of Formula (III), A¹ is N; B¹ is R¹; and D¹ is H.

In one embodiment of Formula (III), E¹ is H. In another embodiment ofFormula (III), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H.In another embodiment of Formula (III), A¹ is C(A²); A² is H; B¹ isNHR¹; E¹ is H; and D¹ is Cl. In another embodiment of Formula (III), A¹is C(A²); A² is H; B¹ is OR¹; D¹ is H; and E¹ is H. In anotherembodiment of Formula (III), A¹ is C(A²); A² is H; B¹ is Cl; D¹ is H;and E¹ is H. In another embodiment of Formula (III), A¹ is C(A²); A² isH; B¹ is R¹; D¹ is H; and E¹ is H. In another embodiment of Formula(III), A¹ is N; B¹ is NHR¹; D¹ is H; and E¹ is H. In another embodimentof Formula (III), A¹ is N; B¹ is NHR¹; E¹ is H; and D¹ is Cl. In anotherembodiment of Formula (III), A¹ is N; B¹ is OR¹; D¹ is H; and E¹ is H.In another embodiment of Formula (III), A¹ is N; B¹ is Cl; D¹ is H; andE¹ is H. In another embodiment of Formula (III), A¹ is N; B¹ is R¹; D¹is H; and E¹ is H.

In one embodiment of Formula (III), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, or C(O)NH₂. In another embodiment of Formula(III), Y¹ is H. In another embodiment of Formula (III), Y¹ is CN. Inanother embodiment of Formula (III), Y¹ is F, Cl, Br, or I. In anotherembodiment of Formula (III), Y¹ is CF₃. In another embodiment of Formula(III), Y¹ is SR¹⁷. In another embodiment of Formula (III), Y¹ is OR¹⁷.In another embodiment of Formula (III), Y¹ is NO₂. In another embodimentof Formula (III), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. Inanother embodiment of Formula (III), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl.In another embodiment of Formula (III), Y¹ is R¹⁷; wherein R¹⁷ isalkynyl. In another embodiment of Formula (III), A¹ is C(A²); A² is H;B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ isalkyl or alkynyl. In another embodiment of Formula (III), A¹ is C(A²);A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In anotherembodiment of Formula (III), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H;E¹ is H; and Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl substituted with threeF. In another embodiment of Formula (III), A¹ is N; B¹ is NHR¹; D¹ is H;E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl. Inanother embodiment of Formula (III), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ isH; and Y¹ is NO₂. In another embodiment of Formula (III), A¹ is N; B¹ isNHR¹; D¹ is H; E¹ is H; and Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkylsubstituted with three F.

In one embodiment of Formula (III), Y¹ and B¹, together with the atomsto which they are attached, are benzene. In another embodiment ofFormula (III), Y¹ and B¹, together with the atoms to which they areattached, are heteroarene. In another embodiment of Formula (III), A¹ isC(A²); A², G¹, E¹, and D¹ are independently selected H; and Y¹ and B¹,together with the atoms to which they are attached, are benzene. Inanother embodiment of Formula (III), A¹ is C(A²); A², G¹, E¹, and D¹ areindependently selected H; and Y¹ and B¹, together with the atoms towhich they are attached, are heteroarene.

In one embodiment of Formula (III), R¹ is R⁴ or R⁵. In one embodiment ofFormula (III), R¹ is R⁴. In one embodiment of Formula (III), R¹ is R⁵.In one embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl. In one embodimentof Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl or heterocycloalkyl. Inone embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl. In oneembodiment of Formula (III), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷ or N(R⁵⁷)₂. In another embodiment ofFormula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (III), R¹ is R⁴;R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (III), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl. Inanother embodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. In anotherembodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂. In another embodiment of Formula (III), R¹ isR⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; andwherein the cyclohexyl ring is substituted with N(R⁵⁷)₂; R⁵⁷ is R⁶¹; andR⁶¹ is alkyl which is unsubstituted or substituted with R⁶². In anotherembodiment of Formula (III), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with R⁵⁷; R¹⁷ is R⁶¹; and R⁶¹ is alkyl which isunsubstituted or substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ iscycloalkyl. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkylwhich is substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ is cyclopropyl.

In one embodiment of Formula (III), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein R⁴ is unsubstituted or substituted as definedherein. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is substituted asdefined herein. In another embodiment of Formula (III), R¹ is R⁴; and R⁴is heterocycloalkyl; wherein the heterocycloalkyl ring is substitutedwith R⁵⁷. In another embodiment of Formula (III), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperdinyl orpiperizinyl; and wherein the heterocycloalkyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰ or R⁶¹. In another embodiment of Formula (III), R¹is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring ispiperdinyl or piperizinyl; and wherein the piperdinyl or piperizinylring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰ or R⁶¹; R⁶⁰ isheterocycloalkyl; and R⁶¹ is alkyl. In another embodiment of Formula(III), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkylring is piperdinyl or piperizinyl; and wherein the piperdinyl orpiperizinyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl is tetrahydropyranyl. Inanother embodiment of Formula (III), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperdinyl or piperizinyl; andwherein the piperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷is R⁶¹; R⁶¹ is alkyl; and the alkyl is methyl. In another embodiment ofFormula (III), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein thepiperdinyl or piperizinyl ring is substituted with C(O)OR⁵⁷; R⁵⁷ is R⁶¹;R⁶¹ is alkyl; and the alkyl is methyl.

In one embodiment of Formula (III), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (III), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,OH, CN, or F. In another embodiment of Formula (III), R¹ is R⁵; and R⁵is alkyl which is substituted with R⁷, OR⁷, NHR⁷, or N(R⁷)₂.

In one embodiment of Formula (III), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (III), R⁷ is R⁸ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (III), R⁷ is R⁹ which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (III), R⁷ is R¹⁰ which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (III), R⁸ is R¹¹ whichis unsubstituted or substituted as defined herein.

In one embodiment of Formula (III), R⁸ is phenyl which is unsubstitutedor substituted as defined herein.

In one embodiment of Formula (III), R⁹ is heteroaryl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (III), R⁹ is furanyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (III), R⁹ is furanyl;which is unsubstituted.

In one embodiment of Formula (III), R¹⁰ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, heterocycloalkyl which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (III), R¹⁰ is heterocycloalkyl which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (III),R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,oxetanyl, piperdinyl, or pyrrolidinyl, which are unsubstituted orsubstituted as defined herein. In another embodiment of Formula (III),R¹⁰ is tetrahydropyranyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (III), R¹⁰ ismorpholinyl; which is unsubstituted or substituted as defined herein. Inanother embodiment of Formula (III), R¹⁰ is cycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (III), R¹⁰ is cycloalkyl which is unsubstituted or substitutedas defined herein. In another embodiment of Formula (III), R¹⁰ iscyclohexyl, cyclopropyl, cyclobutyl, or bicyclo[2.2.1]heptanyl; which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (III), R¹⁰ is heterocycloalkyl which is fused with R^(10A); andR^(10A) is heteroarene. In another embodiment of Formula (III), R¹⁰ is5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl.

In one embodiment of Formula (III), R¹¹ is alkyl, alkenyl or alkynylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (III), R¹¹ is alkyl. In another embodiment ofFormula (III), R¹¹ is methyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (III), R¹¹ is alkyl;which is substituted as defined herein. In another embodiment of Formula(III), R¹¹ is alkyl; which is substituted with R¹², OR¹², or CF₃. Inanother embodiment of Formula (III), R¹¹ is alkyl; which is substitutedwith OR¹²; R¹² is R¹⁶; and R¹⁶ is alkyl. In another embodiment ofFormula (III), R¹¹ is alkyl; which is substituted with CF₃. In anotherembodiment of Formula (III), R¹¹ is alkyl; which is substituted withR¹²; R¹² is R¹⁴; and R¹⁴ is heteroaryl.

In one embodiment of Formula (III),

n, p, r, and q are each 0;

A¹ is N or C(A²);

A² is H, F, Br, I, or Cl;

B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Br, I or Cl;

D¹ is H, F, Br, I, or Cl;

E¹ is H; and

Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃, R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, orC(O)NH₂; or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, heteroarene, or heterocycloalkene; and

A², D¹, and E¹ are independently selected H;

R¹ is R⁴ or R⁵;

R⁴ is cycloalkyl, or heterocycloalkyl;

R⁵ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R⁷, OR⁷, NHR⁷,N(R⁷)₂, CN, OH, F, Cl, Br or I;

R⁷ is R⁸, R⁹, R¹⁰, or R¹¹;

R⁸ is phenyl;

R⁹ is heteroaryl;

R¹⁰ is cycloalkyl, cycloalkenyl, or heterocycloalkyl; each of which isunfused or fused with R^(10A), R^(10A) is heteroarene;

R¹¹ is alkyl each of which is unsubstituted or substituted with one ortwo or three of independently selected R¹², OR¹² or CF₃;

R¹² is R¹⁴ or R¹⁶;

R¹⁴ is heteroaryl;

R¹⁶ is alkyl;

R¹⁷ is R²¹;

R²¹ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R²², F, Cl, Br or I;

R²² is R²⁵;

R²⁵ is heterocycloalkyl;

wherein the cyclic moieties represented by Y¹ and B¹ together, R⁴, R⁸,R¹⁰, and R²⁵, are independently unsubstituted, further unsubstituted,substituted or further substituted with one or two or three or four orfive of independently selected R^(57A), R⁵⁷, OR⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷,CO(O)R⁵⁷, C(O)N(R⁵⁷)₂, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁷, NHS(O)₂R⁵⁷, OH,CN, (O), F, Cl, Br or I;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl;

R⁶⁰ is cycloalkyl, or heterocycloalkyl;

R⁶¹ is alkyl which is unsubstituted or substituted with one or two orthree of independently selected R⁶², OR⁶², N(R⁶²)₂, C(O)OH, CN, F, Cl,Br or I;

R⁶² is R⁶⁵, or R⁶⁶;

R⁶⁵ is cycloalkyl, or heterocycloalkyl;

R⁶⁶ is alkyl which is unsubstituted or substituted with OR⁶⁷;

R⁶⁷ is alkyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, and R⁶⁰ areunsubstituted or substituted with one or two or three or four ofindependently selected R⁶⁸, F, Cl, Br or I;

R⁶⁸ is R⁷¹ or R⁷²;

R⁷¹ is heterocycloalkyl; and

R⁷² is alkyl, which is unsubstituted or substituted with one or two F.

Still another embodiment pertains to compounds having Formula (III),which are

-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(2-naphthylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   5-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethoxy)nicotinamide;-   N-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-bromo-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-oxo-3,4-dihydroquinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}morpholine-4-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-3-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yl    oxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S,3R)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,3S)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[cis-3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide;-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide;-   Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[trans-4-(fluoromethyl)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclobutylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-2-oxopiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylazetidin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-cyclopropylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclobutylmorpholin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydrofuran-3-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(trifluoromethoxy)benzyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxaspiro[4.5]dec-8-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[cis-3-morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-fluoro-1-(methylsulfonyl)piperidin-4-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[3-(dimethylamino)propoxy]benzyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(E)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(Z)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   (2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholin-4-yl)acetic    acid;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   ethyl    4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)piperazine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(2-methoxyethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   tert-butyl    4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]piperazine-1-carboxylate;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-(pentafluoro-λ⁶-sulfanyl)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(oxetan-3-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3R)-tetrahydrofuran-3-ylamino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(oxetan-3-yl)azetidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(3-furylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-chloro-6-[2-(tetrahydrofuran-2-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(cyclopropylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-chloro-6-(2-methoxyethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(methoxyacetyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide;-   N-({5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(trans-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(cis-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(1,3-thiazol-5-ylmethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-chloro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl)phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,5-difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,4-difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   methyl    2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholine-4-carboxylate;-   2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}phenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   (2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   N-[(5-chloro-6-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2,2-difluorocyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(2-oxaspiro[3.5]non-7-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-cyano-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2-oxaspiro[3.5]non-7-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-cyano-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   N-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)morpholine-4-carboxamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methoxymethyl)cyclohexyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-chloro-6-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;    and therapeutically acceptable salts, and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(IV)

and therapeutically acceptable salts, and metabolites thereof,wherein A¹, B¹, D¹, E¹, and Y¹ are as described herein for Formula (I);R¹⁰⁰ is as described for substituents on R²⁶; n is 0, 1, 2, or 3; R¹ isas described for substituents on R³⁰; p is 0, 1, 2, 3, 4, 5, or 6; R¹⁰⁴is as described for substituents on R³⁸; s is 0, 1, 2, 3, 4, 5, or 6;R¹⁰³ is as described for substituents on R⁵⁸; and r is 0, 1, 2, 3, or 4.

In one embodiment of Formula (IV), n, p, r, and s are each 0.

In one embodiment of Formula (IV), A¹ is N. In another embodiment ofFormula (IV), A¹ is C(A²). In another embodiment of Formula (IV), A¹ isC(A²); and A² is H, F, Cl, Br, or I. In another embodiment of Formula(IV), A¹ is C(A²); and A² is H.

In one embodiment of Formula (IV), B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Cl,Br, or I. In another embodiment of Formula (IV), A¹ is C(A²); A² is H;and B¹ is NHR¹. In another embodiment of Formula (IV), A¹ is C(A²); A²is H; and B¹ is OR¹. In another embodiment of Formula (IV), A¹ is C(A²);A² is H; and B¹ is Cl. In another embodiment of Formula (IV), A¹ isC(A²); A² is H; and B¹ is R¹. In another embodiment of Formula (IV), A¹is N; and B¹ is NHR¹. In another embodiment of Formula (IV), A¹ is N;and B¹ is OR¹. In another embodiment of Formula (IV), A¹ is N; and B¹ isCl. In another embodiment of Formula (IV), A¹ is N; and B¹¹ is R¹.

In one embodiment of Formula (IV), D¹ is H or Cl. In another embodimentof Formula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H. Inanother embodiment of Formula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹;and D¹ is Cl. In another embodiment of Formula (IV), A¹ is C(A²); A² isH; B¹ is OR¹; and D¹ is H. In another embodiment of Formula (IV), A¹ isC(A²); A² is H; B¹ is Cl; and D¹ is H. In another embodiment of Formula(IV), A¹ is C(A²); A² is H; B¹ is R¹; and D¹ is H. In another embodimentof Formula (IV), A¹ is N; B¹ is NHR¹; and D¹ is H. In another embodimentof Formula (IV), A¹ is N; B¹ is NHR¹; and D¹ is Cl. In anotherembodiment of Formula (IV), A¹ is N; B¹ is OR¹; and D¹ is H. In anotherembodiment of Formula (IV), A¹ is N; B¹ is Cl; and D¹ is H. In anotherembodiment of Formula (IV), A¹ is N; B¹ is R¹; and D¹ is H.

In one embodiment of Formula (IV), E¹ is H. In another embodiment ofFormula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹; E¹is H; and D¹ is Cl. In another embodiment of Formula (IV), A¹ is C(A²);A² is H; B¹ is OR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (IV), A¹ is C(A²); A² is H; B¹ is Cl; D¹ is H; and E¹ is H. Inanother embodiment of Formula (IV), A¹ is C(A²); A² is H; B¹ is R¹; D¹is H; and E¹ is H. In another embodiment of Formula (IV), A¹ is N; B¹ isNHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (IV), A¹ isN; B¹ is NHR¹; E¹ is H; and D¹ is Cl. In another embodiment of Formula(IV), A¹ is N; B¹ is OR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (IV), A¹ is N; B¹ is Cl; D¹ is H; and E¹ is H. In anotherembodiment of Formula (IV), A¹ is N; B¹ is R¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (IV), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, or C(O)NH₂. In another embodiment of Formula(IV), Y¹ is H. In another embodiment of Formula (IV), Y¹ is CN. Inanother embodiment of Formula (IV), Y¹ is F, Cl, Br, or I. In anotherembodiment of Formula (IV), Y¹ is CF₃. In another embodiment of Formula(IV), Y¹ is SR¹⁷. In another embodiment of Formula (IV), Y¹ is OR¹⁷. Inanother embodiment of Formula (IV), Y¹ is NO₂. In another embodiment ofFormula (IV), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (IV), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (IV), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl.In another embodiment of Formula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl oralkynyl. In another embodiment of Formula (IV), A¹ is C(A²); A² is H; B¹is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment ofFormula (IV), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹is SO₂R¹⁷; wherein R¹⁷ is alkyl substituted with three F. In anotherembodiment of Formula (IV), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; andY¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl. In anotherembodiment of Formula (IV), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; andY¹ is NO₂. In another embodiment of Formula (IV), A¹ is N; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl substitutedwith three F.

In one embodiment of Formula (IV), Y¹ and B¹, together with the atoms towhich they are attached, are benzene. In another embodiment of Formula(IV), Y¹ and B¹, together with the atoms to which they are attached, areheteroarene. In another embodiment of Formula (IV), A¹ is C(A²); A², G¹,E¹, and D¹ are independently selected H; and Y¹ and B¹, together withthe atoms to which they are attached, are benzene. In another embodimentof Formula (IV), A¹ is C(A²); A², G¹, E¹, and D¹ are independentlyselected H; and Y¹ and B¹, together with the atoms to which they areattached, are heteroarene.

In one embodiment of Formula (IV), R¹ is R⁴ or R⁵. In one embodiment ofFormula (IV), R¹ is R⁴. In one embodiment of Formula (IV), R¹ is R⁵. Inone embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl. In one embodimentof Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl or heterocycloalkyl. Inone embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl. In oneembodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷ or N(R⁵⁷)₂. In another embodiment ofFormula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (IV), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (IV), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl. Inanother embodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. In anotherembodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂. In another embodiment of Formula (IV), R¹ isR⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; andwherein the cyclohexyl ring is substituted with N(R⁵⁷)₂; R⁵⁷ is R⁶¹; andR⁶¹ is alkyl which is unsubstituted or substituted with R⁶². In anotherembodiment of Formula (IV), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with R⁵⁷; R¹⁷ is R⁶¹; and R⁶¹ is alkyl which isunsubstituted or substituted with R⁶², R⁶² is R⁶⁵; and R⁶⁵ iscycloalkyl. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkylwhich is substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ is cyclopropyl

In one embodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (IV), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is substituted as defined herein. Inanother embodiment of Formula (IV), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is substituted withR⁵⁷. In another embodiment of Formula (IV), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperdinyl orpiperizinyl; and wherein the heterocycloalkyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰ or R⁶¹. In another embodiment of Formula (IV), R¹ isR⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring ispiperdinyl or piperizinyl; and wherein the piperdinyl or piperizinylring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰ or R⁶¹; R⁶⁰ isheterocycloalkyl; and R⁶¹ is alkyl. In another embodiment of Formula(IV), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkylring is piperdinyl or piperizinyl; and wherein the piperdinyl orpiperizinyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl is tetrahydropyranyl. Inanother embodiment of Formula (IV), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperdinyl or piperizinyl; andwherein the piperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷is R⁶¹; R⁶¹ is alkyl; and the alkyl is methyl. In another embodiment ofFormula (IV), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein thepiperdinyl or piperizinyl ring is substituted with C(O)OR⁵⁷; R⁵⁷ is R⁶¹;R⁶¹ is alkyl; and the alkyl is methyl.

In one embodiment of Formula (IV), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (IV), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,OH, CN, or F. In another embodiment of Formula (IV), R¹ is R⁵; and R⁵ isalkyl which is substituted with R⁷, OR⁷, NHR⁷, or N(R⁷)₂.

In one embodiment of Formula (IV), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R⁷ is R⁸ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (IV), R⁷ is R⁹ which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (IV), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodiment of Formula (IV), R⁸ is phenyl which is unsubstitutedor substituted as defined herein.

In one embodiment of Formula (IV), R⁹ is heteroaryl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R⁹ is furanyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (IV), R⁹ is furanyl;which is unsubstituted.

In one embodiment of Formula (IV), R¹⁰ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, heterocycloalkyl which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R¹⁰ is heterocycloalkyl which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (IV),R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,oxetanyl, piperdinyl, or pyrrolidinyl, which are unsubstituted orsubstituted as defined herein. In another embodiment of Formula (IV),R¹⁰ is tetrahydropyranyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (IV), R¹⁰ ismorpholinyl; which is unsubstituted or substituted as defined herein. Inanother embodiment of Formula (IV), R¹⁰ is cycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R¹⁰ is cycloalkyl which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (IV), R¹⁰ iscyclohexyl, cyclopropyl, cyclobutyl, or bicyclo[2.2.1]heptanyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (IV), R¹⁰ is heterocycloalkyl which is fused with R^(10A); andR^(10A) is heteroarene. In another embodiment of Formula (IV), R¹⁰ is5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl.

In one embodiment of Formula (IV), R¹¹ is alkyl, alkenyl or alkynylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (IV), R¹¹ is alkyl. In another embodiment ofFormula (IV), R¹¹ is methyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (IV), R¹¹ is alkyl;which is substituted as defined herein. In another embodiment of Formula(IV), R¹¹ is alkyl; which is substituted with R¹², OR¹², or CF₃. Inanother embodiment of Formula (IV), R¹¹ is alkyl; which is substitutedwith OR¹²; R¹² is R¹⁶; and R¹⁶ is alkyl. In another embodiment ofFormula (IV), R¹¹ is alkyl; which is substituted with CF₃. In anotherembodiment of Formula (IV), R¹¹ is alkyl; which is substituted with R¹²,R¹² is R¹⁴, and R¹⁴ is heteroaryl.

In one embodiment of Formula (IV),

n, p, r, and s are each 0;

A¹ is N or C(A²);

A² is H, F, Br, I, or Cl;

B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Br, I or Cl;

D¹ is H, F, Br, I, or Cl;

E¹ is H; and

Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃, R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, orC(O)NH₂; or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, heteroarene, or heterocycloalkene; and

A², D¹, and E¹ are independently selected H;

R¹ is R⁴ or R⁵;

R⁴ is cycloalkyl, or heterocycloalkyl;

R⁵ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R⁷, OR⁷, NHR⁷,N(R⁷)₂, CN, OH, F, Cl, Br or I;

R⁷ is R⁸, R⁹, R¹⁰, or R¹¹;

R⁸ is phenyl;

R⁹ is heteroaryl;

R¹⁰ is cycloalkyl, cycloalkenyl, or heterocycloalkyl; each of which isunfused or fused with R^(10A), R^(10A) is heteroarene;

R¹¹ is alkyl each of which is unsubstituted or substituted with one ortwo or three of independently selected R¹², OR¹² or CF₃;

R¹² is R¹⁴ or R¹⁶;

R¹⁴ is heteroaryl;

R¹⁶ is alkyl;

R¹⁷ is R²¹;

R²¹ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R²², F, Cl, Br or I;

R²² is R²⁵;

R²⁵ is heterocycloalkyl;

wherein the cyclic moieties represented by Y¹ and B¹ together, R⁴, R⁸,R¹⁰, and R²⁵, are independently unsubstituted, further unsubstituted,substituted or further substituted with one or two or three or four orfive of independently selected R^(57A), R⁵⁷, OR⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷,CO(O)R⁵⁷, C(O)N(R⁵⁷)₂, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁷, NHS(O)₂R⁵⁷, OH,CN, (O), F, Cl, Br or I;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl;

R⁶⁰ is cycloalkyl, or heterocycloalkyl;

R⁶¹ is alkyl which is unsubstituted or substituted with one or two orthree of independently selected R⁶², OR⁶², N(R⁶²)₂, C(O)OH, CN, F, Cl,Br or I;

R⁶² is R⁶⁵, or R⁶⁶;

R⁶⁵ is cycloalkyl, or heterocycloalkyl;

R⁶⁶ is alkyl which is unsubstituted or substituted with OR⁶⁷;

R⁶⁷ is alkyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, and R⁶⁰ areunsubstituted or substituted with one or two or three or four ofindependently selected R⁶⁸, F, Cl, Br or I;

R⁶⁸ is R⁷¹ or R⁷²;

R⁷¹ is heterocycloalkyl; and

R⁷² is alkyl, which is unsubstituted or substituted with one or two F.

Still another embodiment pertains to compounds having Formula (IV),which are4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;and therapeutically acceptable salts, and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(V)

and therapeutically acceptable salts, and metabolites thereof,wherein A¹, B¹, D¹, E¹, and Y¹ are as described herein for Formula (I);R¹⁰⁰ is as described for substituents on R²⁶; n is 0, 1, 2, or 3; R¹⁰¹is as described for substituents on R³⁰; p is 0, 1, 2, 3, 4, 5, or 6;R¹⁰⁵ is as described for substituents on R⁴⁰; t is 0, 1, 2, 3, or 4;R¹⁰³ is as described for substituents on R⁵⁸; and r is 0, 1, 2, 3, or 4.

In one embodiment of Formula (V), n, p, r, and t are each 0.

In one embodiment of Formula (V), A¹ is N. In another embodiment ofFormula (V), A¹ is C(A²). In another embodiment of Formula (V), A¹ isC(A²); and A² is H, F, Cl, Br, or I. In another embodiment of Formula(V), A¹ is C(A²); and A² is H.

In one embodiment of Formula (V), B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Cl,Br, or I. In another embodiment of Formula (V), A¹ is C(A²); A² is H;and B¹ is NHR¹. In another embodiment of Formula (V), A¹ is C(A²); A² isH; and B¹ is OR¹. In another embodiment of Formula (V), A¹ is C(A²); A²is H; and B¹ is Cl. In another embodiment of Formula (V), A¹ is C(A²);A² is H; and B¹ is R¹. In another embodiment of Formula (V), A¹ is N;and B¹ is NHR¹. In another embodiment of Formula (V), A¹ is N; and B¹ isOR¹. In another embodiment of Formula (V), A¹ is N; and B¹ is Cl. Inanother embodiment of Formula (V), A¹ is N; and B¹ is R¹.

In one embodiment of Formula (V), D¹ is H or Cl. In another embodimentof Formula (V), A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H. Inanother embodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is NHR¹; andD¹ is Cl. In another embodiment of Formula (V), A¹ is C(A²); A² is H; B¹is OR¹; and D¹ is H. In another embodiment of Formula (V), A¹ is C(A²);A² is H; B¹ is Cl; and D¹ is H. In another embodiment of Formula (V), A¹is C(A²); A² is H; B¹ is R¹; and D¹ is H. In another embodiment ofFormula (V), A¹ is N; B¹ is NHR¹; and D¹ is H. In another embodiment ofFormula (V), A¹ is N; B¹ is NHR¹; and D¹ is Cl. In another embodiment ofFormula (V), A¹ is N; B¹ is OR¹; and D¹ is H. In another embodiment ofFormula (V), A¹ is N; B¹ is Cl; and D¹ is H. In another embodiment ofFormula (V), A¹ is N; B¹ is R¹; and D¹ is H.

In one embodiment of Formula (V), E¹ is H. In another embodiment ofFormula (V), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is NHR¹; E¹is H; and D¹ is Cl. In another embodiment of Formula (V), A¹ is C(A²);A² is H; B¹ is OR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (V), A¹ is C(A²); A² is H; B¹ is Cl; D¹ is H; and E¹ is H. Inanother embodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is R¹; D¹ isH; and E¹ is H. In another embodiment of Formula (V), A¹ is N; B¹ isNHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (V), A¹ isN; B¹ is NHR¹; E¹ is H; and D¹ is Cl. In another embodiment of Formula(V), A¹ is N; B¹ is OR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (V), A¹ is N; B¹ is Cl; D¹ is H; and E¹ is H. In anotherembodiment of Formula (V), A¹ is N; B¹ is R¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (V), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, or C(O)NH₂. In another embodiment of Formula(V), Y¹ is H. In another embodiment of Formula (V), Y¹ is CN. In anotherembodiment of Formula (V), Y¹ is F, Cl, Br, or I. In another embodimentof Formula (V), Y¹ is CF₃. In another embodiment of Formula (V), Y¹ isSR¹⁷. In another embodiment of Formula (V), Y¹ is OR¹⁷. In anotherembodiment of Formula (V), Y¹ is NO₂. In another embodiment of Formula(V), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (V), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (V), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl. Inanother embodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl.In another embodiment of Formula (V), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment of Formula (V),A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is SO₂R¹⁷;wherein R¹⁷ is alkyl substituted with three F. In another embodiment ofFormula (V), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂ orSO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl. In another embodiment ofFormula (V), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. Inanother embodiment of Formula (V), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ isH; and Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl substituted with three F.

In one embodiment of Formula (V), Y¹ and B¹, together with the atoms towhich they are attached, are benzene. In another embodiment of Formula(V), Y¹ and B¹, together with the atoms to which they are attached, areheteroarene. In another embodiment of Formula (V), A¹ is C(A²); A², G¹,E¹, and D¹ are independently selected H; and Y¹ and B¹, together withthe atoms to which they are attached, are benzene. In another embodimentof Formula (V), A¹ is C(A²); A², G¹, E¹, and D¹ are independentlyselected H; and Y¹ and B¹, together with the atoms to which they areattached, are heteroarene.

In one embodiment of Formula (V), R¹ is R⁴ or R⁵. In one embodiment ofFormula (V), R¹ is R⁴. In one embodiment of Formula (V), R¹ is R⁵. Inone embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl. In one embodimentof Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl or heterocycloalkyl. Inone embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl. In oneembodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷ or N(R⁵⁷)₂. In another embodiment ofFormula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ringis cyclohexyl; and wherein the cyclohexyl ring is substituted with R⁵⁷;and R⁵⁷ is R⁶⁰. In another embodiment of Formula (V), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (V), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl. Inanother embodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂. In another embodiment of Formula (V), R¹ isR⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; andwherein the cyclohexyl ring is substituted with N(R⁵⁷)₂; R⁵⁷ is R⁶¹; andR⁶¹ is alkyl which is unsubstituted or substituted with R⁶². In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with R⁵⁷; R¹⁷ is R⁶¹; and R⁶¹ is alkyl which isunsubstituted or substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ iscycloalkyl. In another embodiment of Formula (V), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkylwhich is substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ is cyclopropyl

In one embodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is substituted as defined herein. In anotherembodiment of Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl; whereinthe heterocycloalkyl ring is substituted with R⁵⁷. In another embodimentof Formula (V), R¹ is R⁴; and R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein theheterocycloalkyl ring is substituted with R⁵⁷; and R⁵⁷ is R⁶⁰ or R⁶¹. Inanother embodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperdinyl or piperizinyl; andwherein the piperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷is R⁶⁰ or R⁶¹; R⁶⁰ is heterocycloalkyl; and R⁶¹ is alkyl. In anotherembodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein thepiperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰is heterocycloalkyl; wherein the heterocycloalkyl is tetrahydropyranyl.In another embodiment of Formula (V), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperdinyl or piperizinyl; andwherein the piperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷is R⁶¹; R⁶¹ is alkyl; and the alkyl is methyl. In another embodiment ofFormula (V), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein thepiperdinyl or piperizinyl ring is substituted with C(O)OR⁵⁷; R⁵⁷ is R⁶¹;R⁶¹ is alkyl; and the alkyl is methyl.

In one embodiment of Formula (V), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (V), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,OH, CN, or F. In another embodiment of Formula (V), R¹ is R⁵; and R⁵ isalkyl which is substituted with R⁷, OR⁷, NHR⁷, or N(R⁷)₂.

In one embodiment of Formula (V), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R⁷ is R⁸ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (V), R⁷ is R⁹ which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (V), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodiment of Formula (V), R⁸ is phenyl which is unsubstituted orsubstituted as defined herein.

In one embodiment of Formula (V), R⁹ is heteroaryl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R⁹ is furanyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (V), R⁹ is furanyl;which is unsubstituted.

In one embodiment of Formula (V), R¹⁰ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, heterocycloalkyl which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (V), R¹⁰ is heterocycloalkyl which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (V), R¹⁰is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,oxetanyl, piperdinyl, or pyrrolidinyl, which are unsubstituted orsubstituted as defined herein. In another embodiment of Formula (V), R¹⁰is tetrahydropyranyl; which is unsubstituted or substituted as definedherein. In another embodiment of Formula (V), R¹⁰ is morpholinyl; whichis unsubstituted or substituted as defined herein. In another embodimentof Formula (V), R¹⁰ is cycloalkyl which is unsubstituted or substitutedas defined herein. In another embodiment of Formula (V), R¹⁰ iscycloalkyl which is unsubstituted or substituted as defined herein. Inanother embodiment of Formula (V), R¹⁰ is cyclohexyl, cyclopropyl,cyclobutyl, or bicyclo[2.2.1]heptanyl; which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (V), R¹⁰is heterocycloalkyl which is fused with R^(10A); and R^(10A) isheteroarene. In another embodiment of Formula (V), R¹⁰ is5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl.

In one embodiment of Formula (V), R¹¹ is alkyl, alkenyl or alkynyl whichare unsubstituted or substituted as defined herein. In anotherembodiment of Formula (V), R¹¹ is alkyl. In another embodiment ofFormula (V), R¹¹ is methyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (V), R¹¹ is alkyl;which is substituted as defined herein. In another embodiment of Formula(V), R¹¹ is alkyl; which is substituted with R¹², OR¹², or CF₃. Inanother embodiment of Formula (V), R¹¹ is alkyl; which is substitutedwith OR¹²; R¹² is R¹⁶; and R¹⁶ is alkyl. In another embodiment ofFormula (V), R¹¹ is alkyl; which is substituted with CF₃. In anotherembodiment of Formula (V), R¹¹ is alkyl; which is substituted with R¹²;R¹² is R¹⁴; and R¹¹ is heteroaryl.

In one embodiment of Formula (V),

n, p, r, and t are each 0;

A¹ is N or C(A²);

A² is H, F, Br, I, or Cl;

B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Br, I or Cl;

D¹ is H, F, Br, I, or Cl;

E¹ is H; and

Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃, R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, orC(O)NH₂; or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, heteroarene, or heterocycloalkene; and

A², D¹, and E¹ are independently selected H;

R¹ is R⁴ or R⁵;

R⁴ is cycloalkyl, or heterocycloalkyl;

R⁵ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R⁷, OR⁷, NHR⁷,N(R⁷)₂, CN, OH, F, Cl, Br or I;

R⁷ is R⁸, R⁹, R¹⁰, or R¹¹;

R⁸ is phenyl;

R⁹ is heteroaryl;

R¹⁰ is cycloalkyl, cycloalkenyl, or heterocycloalkyl; each of which isunfused or fused with R^(10A), R^(10A) is heteroarene;

R¹¹ is alkyl each of which is unsubstituted or substituted with one ortwo or three of independently selected R¹², OR¹² or CF₃;

R¹² is R¹⁴ or R¹⁶;

R¹⁴ is heteroaryl;

R¹⁶ is alkyl;

R¹⁷ is R²¹;

R²¹ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R²², F, Cl, Br or I;

R²² is R²⁵;

R²⁵ is heterocycloalkyl;

wherein the cyclic moieties represented by Y¹ and B¹ together, R⁴, R⁸,R¹⁰, and R²⁵ are independently unsubstituted, further unsubstituted,substituted or further substituted with one or two or three or four orfive of independently selected R^(57A), R⁵⁷, OR⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷,CO(O)R⁵⁷, C(O)N(R⁵⁷)₂, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁷, NHS(O)₂R⁵⁷, OH,CN, (O), F, Cl, Br or I;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl;

R⁶⁰ is cycloalkyl, or heterocycloalkyl;

R⁶¹ is alkyl which is unsubstituted or substituted with one or two orthree of independently selected R⁶², OR⁶², N(R⁶²)₂, C(O)OH, CN, F, Cl,Br or I;

R⁶² is R⁶⁵, or R⁶⁶;

R⁶⁵ is cycloalkyl, or heterocycloalkyl;

R⁶⁶ is alkyl which is unsubstituted or substituted with OR⁶⁷;

R⁶⁷ is alkyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, and R⁶⁰ areunsubstituted or substituted with one or two or three or four ofindependently selected R⁶⁸, F, Cl, Br or I;

R⁶⁸ is R⁷¹ or R⁷²;

R⁷¹ is heterocycloalkyl; and

R⁷² is alkyl, which is unsubstituted or substituted with one or two F.

Still another embodiment pertains to a compound having Formula (V),which is

-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   and therapeutically acceptable salts, and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(VI)

and therapeutically acceptable salts, and metabolites thereof,wherein A¹, B¹, D¹, E¹, and Y¹ are as described herein for Formula (I);R¹⁰⁰ is as described for substituents on R²⁶; n is 0, 1, 2, or 3; R¹⁰¹is as described for substituents on R³⁰; p is 0, 1, 2, 3, 4, 5, or 6;R¹⁰² is as described for substituents on R⁴⁰; q is 0, 1, 2, 3, 4, 5, or6; R¹⁰³ is as described for substituents on R⁵⁸; and r is 0, 1, 2, 3, or4.

In one embodiment of Formula (VI), n, p, r, and q are each 0.

In one embodiment of Formula (VI), A¹ is N. In another embodiment ofFormula (VI), A¹ is C(A²). In another embodiment of Formula (VI), A¹ isC(A²); and A² is H, F, Cl, Br, or I. In another embodiment of Formula(VI), A¹ is C(A²); and A² is H.

In one embodiment of Formula (VI), B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Cl,Br, or I. In another embodiment of Formula (VI), A¹ is C(A²); A² is H;and B¹ is NHR¹. In another embodiment of Formula (VI), A¹ is C(A²); A²is H; and B¹ is OR¹. In another embodiment of Formula (VI), A¹ is C(A²);A² is H; and B¹ is Cl. In another embodiment of Formula (VI), A¹ isC(A²); A² is H; and B¹ is R¹. In another embodiment of Formula (VI), A¹is N; and B¹ is NHR¹. In another embodiment of Formula (VI), A¹ is N;and B¹ is OR¹. In another embodiment of Formula (VI), A¹ is N; and B¹ isCl. In another embodiment of Formula (VI), A¹ is N; and B¹ is R¹.

In one embodiment of Formula (VI), D¹ is H or Cl. In another embodimentof Formula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹; and D¹ is H. Inanother embodiment of Formula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹;and D¹ is Cl. In another embodiment of Formula (VI), A¹ is C(A²); A² isH; B¹ is OR¹; and D¹ is H. In another embodiment of Formula (VI), A¹ isC(A²); A² is H; B¹ is Cl; and D¹ is H. In another embodiment of Formula(VI), A¹ is C(A²); A² is H; B¹ is R¹; and D¹ is H. In another embodimentof Formula (VI), A¹ is N; B¹ is NHR¹; and D¹ is H. In another embodimentof Formula (VI), A¹ is N; B¹ is NHR¹; and D¹ is Cl. In anotherembodiment of Formula (VI), A¹ is N; B¹ is OR¹; and D¹ is H. In anotherembodiment of Formula (VI), A¹ is N; B¹ is Cl; and D¹ is H. In anotherembodiment of Formula (VI), A¹ is N; B¹ is R¹; and D¹ is H.

In one embodiment of Formula (VI), E¹ is H. In another embodiment ofFormula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; and E¹ is H. Inanother embodiment of Formula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹; E¹is H; and D¹ is Cl. In another embodiment of Formula (VI), A¹ is C(A²);A² is H; B¹ is OR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (VI), A¹ is C(A²); A² is H; B¹ is Cl; D¹ is H; and E¹ is H. Inanother embodiment of Formula (VI), A¹ is C(A²); A² is H; B¹ is R¹; D¹is H; and E¹ is H. In another embodiment of Formula (VI), A¹ is N; B¹ isNHR¹; D¹ is H; and E¹ is H. In another embodiment of Formula (VI), A¹ isN; B¹ is NHR¹; E¹ is H; and D¹ is Cl. In another embodiment of Formula(VI), A¹ is N; B¹ is OR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (VI), A¹ is N; B¹ is Cl; D¹ is H; and E¹ is H. In anotherembodiment of Formula (VI), A¹ is N; B¹ is R¹; D¹ is H; and E¹ is H.

In one embodiment of Formula (VI), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, or C(O)NH₂. In another embodiment of Formula(VI), Y¹ is H. In another embodiment of Formula (VI), Y¹ is CN. Inanother embodiment of Formula (VI), Y¹ is F, Cl, Br, or I. In anotherembodiment of Formula (VI), Y¹ is CF₃. In another embodiment of Formula(VI), Y¹ is SR¹⁷. In another embodiment of Formula (VI), Y¹ is OR¹⁷. Inanother embodiment of Formula (VI), Y¹ is NO₂. In another embodiment ofFormula (VI), Y¹ is SO₂R¹⁷; wherein R¹⁷ is as defined herein. In anotherembodiment of Formula (VI), Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl. Inanother embodiment of Formula (VI), Y¹ is R¹⁷; wherein R¹⁷ is alkynyl.In another embodiment of Formula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl oralkynyl. In another embodiment of Formula (VI), A¹ is C(A²); A² is H; B¹is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂. In another embodiment ofFormula (VI), A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹is SO₂R¹⁷; wherein R¹⁷ is alkyl substituted with three F. In anotherembodiment of Formula (VI), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; andY¹ is NO₂ or SO₂R¹⁷; wherein R¹⁷ is alkyl or alkynyl. In anotherembodiment of Formula (VI), A¹ is N; B¹ is NHR¹; D¹ is H; E¹ is H; andY¹ is NO₂. In another embodiment of Formula (VI), A¹ is N; B¹ is NHR¹;D¹ is H; E¹ is H; and Y¹ is SO₂R¹⁷; wherein R¹⁷ is alkyl substitutedwith three F.

In one embodiment of Formula (IV), Y¹ and B¹, together with the atoms towhich they are attached, are benzene. In another embodiment of Formula(IV), Y¹ and B¹, together with the atoms to which they are attached, areheteroarene. In another embodiment of Formula (IV), A¹ is C(A²); A², G¹,E¹, and D¹ are independently selected H; and Y¹ and B¹, together withthe atoms to which they are attached, are benzene. In another embodimentof Formula (IV), A¹ is C(A²); A², G¹, E¹, and D¹ are independentlyselected H; and Y¹ and B¹, together with the atoms to which they areattached, are heteroarene.

In one embodiment of Formula (VI), R¹ is R⁴ or R⁵. In one embodiment ofFormula (VI), R¹ is R⁴. In one embodiment of Formula (VI), R¹ is R⁵. Inone embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl,cycloalkenyl, heterocycloalkyl or heterocycloalkenyl. In one embodimentof Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl or heterocycloalkyl. Inone embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl. In oneembodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl.

In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is substituted as defined herein. In another embodimentof Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is substituted with R⁵⁷ or N(R⁵⁷)₂. In another embodiment ofFormula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein the cycloalkylring is cyclohexyl; and wherein the cyclohexyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰. In another embodiment of Formula (VI), R¹ is R⁴; R⁴is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and whereinthe cyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; and R⁶⁰ isheterocycloalkyl. In another embodiment of Formula (VI), R¹ is R⁴; R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl ring is morpholinyl. Inanother embodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl;wherein the cycloalkyl ring is substituted with N(R⁵⁷)₂. In anotherembodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with N(R⁵⁷)₂. In another embodiment of Formula (VI), R¹ isR⁴; and R⁴ is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; andwherein the cyclohexyl ring is substituted with N(R⁵⁷)₂; R⁵⁷ is R⁶¹; andR⁶¹ is alkyl which is unsubstituted or substituted with R⁶². In anotherembodiment of Formula (VI), R¹ is R⁴; and R⁴ is cycloalkyl; wherein thecycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring issubstituted with R⁵⁷; R¹⁷ is R⁶¹; and R⁶¹ is alkyl which isunsubstituted or substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ iscycloalkyl. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ iscycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein thecyclohexyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶¹; and R⁶¹ is alkylwhich is substituted with R⁶²; R⁶² is R⁶⁵; and R⁶⁵ is cyclopropyl.

In one embodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein R⁴ is unsubstituted or substituted as defined herein. In anotherembodiment of Formula (VI), R¹ is R⁴; and R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is substituted as defined herein. Inanother embodiment of Formula (VI), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is substituted withR⁵⁷. In another embodiment of Formula (VI), R¹ is R⁴; and R⁴ isheterocycloalkyl; wherein the heterocycloalkyl ring is piperdinyl orpiperizinyl; and wherein the heterocycloalkyl ring is substituted withR⁵⁷; and R⁵⁷ is R⁶⁰ or R⁶¹. In another embodiment of Formula (VI), R¹ isR⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkyl ring ispiperdinyl or piperizinyl; and wherein the piperdinyl or piperizinylring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰ or R⁶¹; R⁶⁰ isheterocycloalkyl; and R⁶¹ is alkyl. In another embodiment of Formula(VI), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein the heterocycloalkylring is piperdinyl or piperizinyl; and wherein the piperdinyl orpiperizinyl ring is substituted with R⁵⁷; R⁵⁷ is R⁶⁰; R⁶⁰ isheterocycloalkyl; wherein the heterocycloalkyl is tetrahydropyranyl. Inanother embodiment of Formula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl;wherein the heterocycloalkyl ring is piperdinyl or piperizinyl; andwherein the piperdinyl or piperizinyl ring is substituted with R⁵⁷; R⁵⁷is R⁶¹; R⁶¹ is alkyl; and the alkyl is methyl. In another embodiment ofFormula (VI), R¹ is R⁴; R⁴ is heterocycloalkyl; wherein theheterocycloalkyl ring is piperdinyl or piperizinyl; and wherein thepiperdinyl or piperizinyl ring is substituted with C(O)OR⁵⁷; R⁵⁷ is R⁶¹;R⁶¹ is alkyl; and the alkyl is methyl.

In one embodiment of Formula (VI), R¹ is R⁵; and R⁵ is alkyl which isunsubstituted or substituted. In one embodiment of Formula (VI), R¹ isR⁵; and R⁵ is alkyl which is unsubstituted or substituted with R⁷, OR⁷,OH, CN, or F. In another embodiment of Formula (VI), R¹ is R⁵; and R⁵ isalkyl which is substituted with R⁷, OR⁷, NHR⁷, or N(R⁷)₂.

In one embodiment of Formula (VI), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹ which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R⁷ is R⁸ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (VI), R⁷ is R⁹ which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R⁷ is R¹⁰ which is unsubstituted or substituted as definedherein. In another embodiment of Formula (VI), R⁷ is R¹¹ which isunsubstituted or substituted as defined herein.

In one embodiment of Formula (VI), R⁸ is phenyl which is unsubstitutedor substituted as defined herein.

In one embodiment of Formula (VI), R⁹ is heteroaryl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R⁹ is furanyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (VI), R⁹ is furanyl;which is unsubstituted.

In one embodiment of Formula (VI), R¹⁰ is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl, heterocycloalkyl which areunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R¹⁰ is heterocycloalkyl which is unsubstituted orsubstituted as defined herein. In another embodiment of Formula (VI),R¹⁰ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,oxetanyl, piperdinyl, or pyrrolidinyl; which are unsubstituted orsubstituted as defined herein. In another embodiment of Formula (VI),R¹⁰ is tetrahydropyranyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (VI), R¹⁰ ismorpholinyl; which is unsubstituted or substituted as defined herein. Inanother embodiment of Formula (VI), R¹⁰ is cycloalkyl which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R¹⁰ is cycloalkyl which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (VI), R¹⁰ iscyclohexyl, cyclopropyl, cyclobutyl, or bicyclo[2.2.1]heptanyl, which isunsubstituted or substituted as defined herein. In another embodiment ofFormula (VI), R¹⁰ is heterocycloalkyl which is fused with R^(10A); andR^(10A) is heteroarene. In another embodiment of Formula (VI), R¹⁰ is5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl.

In one embodiment of Formula (VI), R¹¹ is alkyl, alkenyl or alkynylwhich are unsubstituted or substituted as defined herein. In anotherembodiment of Formula (VI), R¹¹ is alkyl. In another embodiment ofFormula (VI), R¹¹ is methyl; which is unsubstituted or substituted asdefined herein. In another embodiment of Formula (VI), R¹¹ is alkyl;which is substituted as defined herein. In another embodiment of Formula(VI), R¹¹ is alkyl; which is substituted with R¹², OR¹², or CF₃. Inanother embodiment of Formula (VI), R¹¹ is alkyl, which is substitutedwith OR¹²; R¹² is R¹⁶; and R¹⁶ is alkyl. In another embodiment ofFormula (VI), R¹¹ is alkyl; which is substituted with CF₃. In anotherembodiment of Formula (VI), R¹¹ is alkyl, which is substituted with R¹²;R¹² is R¹⁴; and R¹⁴ is heteroaryl.

In one embodiment of Formula (VI),

n, p, r, and q are each 0;

A¹ is N or C(A²);

A² is H, F, Br, I, or Cl;

B¹ is R¹, OR¹, NHR¹, NHC(O)R¹, F, Br, I or Cl;

D¹ is H, F, Br, I, or Cl;

E¹ is H; and

Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃, R¹⁷, OR¹⁷, SR¹⁷, SO₂R¹⁷, orC(O)NH₂; or

Y¹ and B¹, together with the atoms to which they are attached, arebenzene, heteroarene, or heterocycloalkene; and

A², D¹, and E¹ are independently selected H;

R¹ is R⁴ or R⁵;

R⁴ is cycloalkyl, or heterocycloalkyl;

R⁵ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R⁷, OR⁷, NHR⁷,N(R⁷)₂, CN, OH, F, Cl, Br or I;

R⁷ is R⁸, R⁹, R¹⁰, or R¹¹;

R⁸ is phenyl;

R⁹ is heteroaryl;

R¹⁰ is cycloalkyl, cycloalkenyl, or heterocycloalkyl; each of which isunfused or fused with R^(10A), R^(10A) is heteroarene;

R¹¹ is alkyl each of which is unsubstituted or substituted with one ortwo or three of independently selected R¹², OR¹² or CF₃;

R¹² is R¹⁴ or R¹⁶;

R¹⁴ is heteroaryl;

R¹⁶ is alkyl;

R¹⁷ is R²¹;

R²¹ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three of independently selected R²², F, Cl, Br or I;

R²² is R²⁵;

R²⁵ is heterocycloalkyl;

wherein the cyclic moieties represented by Y¹ and B¹ together, R⁴, R⁸,R¹⁰, and R²⁵, are independently unsubstituted, further unsubstituted,substituted or further substituted with one or two or three or four orfive of independently selected R^(57A), R⁵⁷, OR⁵⁷, SO₂R⁵⁷, C(O)R⁵⁷,CO(O)R⁵⁷, C(O)N(R⁵⁷)₂, NH₂, NHR⁵⁷, N(R⁵⁷)₂, NHC(O)R⁷, NHS(O)₂R⁵⁷, OH,CN, (O), F, Cl, Br or I;

R^(57A) is spiroalkyl, or spiroheteroalkyl;

R⁵⁷ is R⁵⁸, R⁶⁰ or R⁶¹;

R⁵⁸ is phenyl;

R⁶⁰ is cycloalkyl, or heterocycloalkyl;

R⁶¹ is alkyl which is unsubstituted or substituted with one or two orthree of independently selected R⁶², OR⁶², N(R⁶²)₂, C(O)OH, CN, F, Cl,Br or I;

R⁶² is R⁶⁵, or R⁶⁶;

R⁶⁵ is cycloalkyl, or heterocycloalkyl;

R⁶⁶ is alkyl which is unsubstituted or substituted with OR⁶⁷;

R⁶⁷ is alkyl;

wherein the cyclic moieties represented by R^(57A), R⁵⁸, and R⁶⁰ areunsubstituted or substituted with one or two or three or four ofindependently selected R⁶⁸, F, Cl, Br or I;

R⁶⁸ is R⁷¹ or R⁷²;

R⁷¹ is heterocycloalkyl; and

R⁷² is alkyl, which is unsubstituted or substituted with one or two F.

Still another embodiment pertains to a compound having Formula (VI),which is

-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;-   and therapeutically acceptable salts, and metabolites thereof.

Pharmaceutical Compositions, Combination Therapies, Methods ofTreatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising acompound having Formula (I) and an excipient.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound having Formula (I).

Still another embodiment comprises methods of treating autoimmunedisease in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which anti-apoptotic Bcl-2 proteins are expressed, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I).

Still another embodiment pertains to methods of treating disease in apatient during which anti-apoptotic Bcl-2 proteins are expressed, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which are expressed anti-apoptotic Bcl-2 proteins, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which are expressed anti-apoptotic Bcl-2 proteins, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositionscomprising an excipient and a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said methods comprisingadministering to the patient a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Metabolites of compounds having Formula (I), produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with anti-apoptotic Bcl-2 proteins.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds having Formula (I) may also have utility for treatingdiseases associated with expression of anti-apoptotic Bcl-2 proteins.

Compounds having Formula (I) may exist as acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring isolation or following purification of the compounds. Acidaddition salts of the compounds are those derived from the reaction ofthe compounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate,glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate,propionate, succinate, tartrate, thiocyanate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds are contemplated as being embraced by this invention. Basicaddition salts of the compounds are those derived from the reaction ofthe compounds with the hydroxide, carbonate or bicarbonate of cationssuch as lithium, sodium, potassium, calcium, and magnesium.

The compounds having Formula (I) may be administered, for example,buccally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperitoneally intrasternally, intravenously,subcutaneously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds having Formula (I) dependon the recipient of the treatment, the disorder being treated and theseverity thereof, the composition containing the compound, the time ofadministration, the route of administration, the duration of treatment,the compound potency, its rate of clearance and whether or not anotherdrug is co-administered. The amount of a compound of this inventionhaving Formula (I) used to make a composition to be administered dailyto a patient in a single dose or in divided doses is from about 0.03 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula (I) may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound havingFormula (I) to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered ophthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered osmotically include, forexample, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered parenterally include,for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil,dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil,peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil,U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered rectally or vaginallyinclude, for example, cocoa butter, polyethylene glycol, wax andmixtures thereof.

Compounds having Formula (I) are expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1)inhibitors, activators of death receptor pathway, Bcr-Abl kinaseinhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drugconjugates, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs,leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growthfactor inhibitors, heat shock protein (HSP)-90 inhibitors, histonedeacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,inhibitors of inhibitors of apoptosis proteins (IAPs), intercalatingantibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors,mammalian target of rapamycin inhibitors, microRNA's, mitogen-activatedextracellular signal-regulated kinase inhibitors, multivalent bindingproteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibitors,retinoids/deltoids, plant alkaloids, small inhibitory ribonucleic acids(siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and thelike, and in combination with one or more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have beenshown to enhance the activity of ABT-263, (i.e.,N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide)or ABT-737 (i.e.,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9),3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan,trofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethynylcytidine, fludarabine, 5-fluorouracil alone or in combinationwith leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN®(melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate,mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol,pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-1,tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,pertuzumab), TAK-165, GW-572016 (Ionafarnib), GW-282974, EKB-569,PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neubispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecificantibodies, mAB AR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptanib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474) and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirubicin, galarubicin, ZAVEDOS® (idarubicin), mitomycin C,nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin,stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and thelike.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxane),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarubicin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzumab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megestrol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), trilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitol (KH1060), fenretinide, PANRETIN® (alitretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMIUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), dacarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(raltitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combretastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EP0906 (epothilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16,18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®, GMK(ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histrelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zoledronic acid), zorubicin and the like.

Data

Determination of the utility of compounds having Formula (I) as bindersto and inhibitors of anti-apoptotic Bcl-2 proteins was performed usingthe Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No.PV4216).

Probe Synthesis

All reagents were used as obtained from the vendor unless otherwisespecified. Peptide synthesis reagents including diisopropylethylamine(DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained fromApplied Biosystems, Inc. (ABI), Foster City, Calif. or AmericanBioanalytical, Natick, Mass. Preloaded 9-Fluorenylmethyloxycarbonyl(Fmoc) amino acid cartridges (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH,Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH,Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH,Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH,Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec,San Jose, Calif. The peptide synthesis resin (Fmoc-Rink amide MBHAresin) and Fmoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego,Calif. Single-isomer 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS)was obtained from Anaspec. Trifluoroacetic acid (TFA) was obtained fromOakwood Products, West Columbia, SC. Thioanisole, phenol,triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) andisopropanol were obtained from Aldrich Chemical Co., Milwaukee, Wis.Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) wererecorded on an Applied Biosystems Voyager DE-PRO MS). Electrospraymass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp.,San Jose, Calif.) in both positive and negative ion mode.

General Procedure for Solid-Phase Peptide Synthesis (SPPS)

Peptides were synthesized with, at most, 250 μmol preloaded WANGresin/vessel on an ABI 433A peptide synthesizer using 250 μmol scaleFASTMOC™ coupling cycles. Preloaded cartridges containing 1 mmolstandard Fmoc-amino acids, except for the position of attachment of thefluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in the cartridge,were used with conductivity feedback monitoring. N-terminal acetylationwas accomplished by using 1 mmol acetic acid in a cartridge understandard coupling conditions.

Removal of 4-Methyltrityl (Mtt) from Lysine

The resin from the synthesizer was washed thrice with DCM and kept wet.150 mL of 95:4:1 dichloromethane:triisopropylsilane:trifluoroacetic acidwas flowed through the resin bed over 30 minutes. The mixture turneddeep yellow then faded to pale yellow. 100 mL of DMF was flowed throughthe bed over 15 minutes. The resin was then washed thrice with DMF andfiltered. Ninhydrin tests showed a strong signal for primary amine.

Resin Labeling With 6-Carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents 6-FAM-NHS in 1% DIEA/DMF andstirred or shaken at ambient temperature overnight. When complete, theresin was drained, washed thrice with DMF, thrice with (1×DCM and 1×methanol) and dried to provide an orange resin that was negative byninhydrin test.

General Procedure for Cleavage and Deprotection of Resin-Bound Peptide

Peptides were cleaved from the resin by shaking for 3 hours at ambienttemperature in a cleavage cocktail consisting of 80% TFA, 5% water, 5%thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1 mL/0.1 g resin). Theresin was removed by filtration and rinsing twice with TFA. The TFA wasevaporated from the filtrates, and product was precipitated with ether(10 mL/0.1 g resin), recovered by centrifugation, washed twice withether (10 mL/0.1 g resin) and dried to give the crude peptide.

General Procedure for Purification of Peptides

The crude peptides were purified on a Gilson preparative HPLC systemrunning Unipoint® analysis software (Gilson, Inc., Middleton, Wis.) on aradial compression column containing two 25×100 mm segments packed withDelta-Pak™ C18 15 μm particles with 100 A pore size and eluted with oneof the gradient methods listed below. One to two milliliters of crudepeptide solution (10 mg/mL in 90% DMSO/water) was purified perinjection. The peaks containing the product(s) from each run were pooledand lyophilized. All preparative runs were run at 20 mL/min with eluentsas buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General Procedure for Analytical HPLC

Analytical HPLC was performed on a Hewlett-Packard 1200 series systemwith a diode-array detector and a Hewlett-Packard 1046A fluorescencedetector running HPLC 3D CHEMSTATION software version A.03.04(Hewlett-Packard. Palo Alto, Calif.) on a 4.6×250 mm YMC column packedwith ODS-AQ 5 m particles with a 120 A pore size and eluted with one ofthe gradient methods listed below after preequilibrating at the startingconditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water andbuffer B: acetonitrile. The flow rate for all gradients was 1 mL/min.

F-Bak: Peptide Probe Acetyl-GQVGRQLAIIGDK(6-FAM)INR-NH₂ (SEQ ID NO:1)

Fmoc-Rink amide MBHA resin was extended using the general peptidesynthesis procedure to provide the protected resin-bound peptide (1.020g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved anddeprotected as described hereinabove to provide the crude product as anorange solid (0.37 g). This product was purified by RP-HPLC. Fractionsacross the main peak were tested by analytical RP-HPLC, and the purefractions were isolated and lyophilized, with the major peak providingthe title compound (0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1[(M+H)⁺].

Alternative Synthesis of Peptide Probe F-Bak: Acetyl-(GQVGRQLAIIGDK(6FAM)INR-NH₂ (SEQ ID NO:1)

The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide MBHAresin (Novabiochem) on an Applied Biosystems 433A automated peptidesynthesizer running FASTMOC™ coupling cycles using pre-loaded 1 mmolamino acid cartridges, except for the fluorescein(6-FAM)-labeled lysine,where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge.The N-terminal acetyl group was incorporated by putting 1 mmol aceticacid in a cartridge and coupling as described hereinabove. Selectiveremoval of the 4-methyltrityl group was accomplished with a solution of95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin over 15 minutes,followed by quenching with a flow of dimethylformamide. Single-isomer6-carboxyfluorescein-NHS was reacted with the lysine side-chain in 1%DIEA in DMF and confirmed complete by ninhydrin testing. The peptide wascleaved from the resin and side-chains deprotected by treating with80:5:5:5:2.5:2.5 TFA/water/phenol/thioanisole/triisopropylsilane:3,6-dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide wasrecovered by precipitation with diethyl ether. The crude peptide waspurified by reverse-phase high-performance liquid chromatography, andits purity and identity were confirmed by analytical reverse-phasehigh-performance liquid chromatography and matrix-assistedlaser-desorption mass-spectrometry (m/z=2137.1 ((M+H)⁺)).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay

Representative compounds were serially diluted in dimethyl sulfoxide(DMSO) starting at 50 μM (2× starting concentration; 10% DMSO) and 10 μLwere transferred into a 384-well plate. Then 10 μL of aprotein/probe/antibody mix was added to each well at finalconcentrations listed in TABLE 1. The samples are then mixed on a shakerfor 1 minute and incubated for an additional 3 hours at roomtemperature. For each assay, the probe/antibody andprotein/probe/antibody were included on each assay plate as negative andpositive controls, respectively. Fluorescence was measured on theENVISION plate reader (Perkin Elmer) using a 340/35 nm excitation filterand 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeled anti-Histidineantibody) emission filters. Dissociation constants (K_(i)) are shown inTABLE 2 below and were determined using Wang's equation (Wang Z.-X., AnExact Mathematical Expression For Describing Competitive Binding Of TwoDifferent Ligands To A Protein Molecule. FEBS Lett. 1995, 360:111-4).

TABLE 1 Protein, Probe And Antibody Used For TR-FRET Assays ProteinProbe Antibody Protein Probe (nM) (nM) Antibody (nM) GST-Bcl-2Peptide Probe F- 1 100 Tb-anti- 1 Bak-Acetyl- GST GQVGRQLAIIGDK(6-FAM)INR-NH₂ (SEQ ID NO: 1) 6-FAM = 6-carboxyfluorescein.; Tb = terbium;GST = glutathione S-transferase

The samples were then mixed on a shaker for 1 minute and incubated foran additional 3 hours at room temperature. For each assay, theprobe/antibody and protein/probe/antibody were included on each assayplate as negative and positive controls, respectively. Fluorescence wasmeasured on the Envision (Perkin Elmer) using a 340/35 nm excitationfilter and 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeledanti-Histidine antibody) emission filters.

Inhibition constants (K_(i)) for compounds according to the inventionare shown in TABLE 2 below. Where the K_(i) for a compound isrepresented as “<” (less than) a certain numerical value, it is intendedto mean that the binding affinity value (e.g., for Bcl-2) is lower thanthe limit of detection of the assay used. Inhibition constants weredetermined using Wang's equation (Wang Zx. An Exact MathematicalExpression For Describing Competitive Binding Of Two Different LigandsTo A Protein Molecule. FEBS Lett. 1995, 360:111-4).

TABLE 2 TR-FRET Bcl-2 Binding K_(i) (μM) EXAMPLE # Ki 1 0.000225 2<0.000010 3 0.000013 4 <0.000010 5 <0.000010 6 0.000018 7 0.00492 80.000153 9 <0.000010 10 <0.000010 11 0.000016 12 <0.000010 13 <0.00001014 0.002798 15 <0.000010 16 0.000219 17 0.00009 18 0.000017 19 0.00022620 0.000181 21 0.000912 22 0.000291 23 0.000083 24 <0.000010 25<0.000010 26 0.000011 27 0.000134 28 <0.000010 29 <0.000010 30 <0.00001031 <0.000010 32 <0.000010 33 <0.000010 34 0.00001 35 <0.000010 360.000017 37 <0.000010 38 0.0003 39 0.000012 40 <0.000010 41 <0.000010 420.000439 43 0.000012 44 <0.000010 45 <0.000010 46 0.000935 47 <0.00001048 <0.000010 49 0.000074 50 0.000021 51 <0.000010 52 0.000114 53<0.000010 54 0.002071 55 <0.000010 56 0.000037 57 0.000063 58 <0.00001059 0.000203 60 <0.000010 61 0.000091 62 <0.000010 63 <0.000010 64<0.000010 65 <0.000010 66 <0.000010 67 <0.000010 68 0.000012 69 0.00115770 0.003964 71 0.00001 72 <0.000010 73 <0.000010 74 0.000029 75<0.000010 76 0.000196 77 0.000213 78 <0.000010 79 <0.000010 80 <0.00001081 <0.000010 82 0.000328 83 0.000071 84 0.000123 85 0.000391 86 0.00049887 0.000618 88 0.000672 89 0.000073 90 0.000013 91 0.000487 92 0.00012893 0.003461 94 0.000678 95 0.000014 96 0.000014 97 0.000017 98 <0.00001099 0.000233 100 <0.000010 101 0.000021 102 0.000094 103 <0.000010 1040.000016 105 <0.000010 106 0.000895 107 0.000035 108 <0.000010 1090.000127 110 0.000557 111 <0.000010 112 <0.000010 113 <0.000010 114<0.000010 115 <0.000010 116 <0.000010 117 <0.000010 118 <0.000010 119<0.000010 120 <0.000010 121 <0.000010 122 <0.000010 123 <0.000010 124<0.000010 125 <0.000010 126 <0.000010 127 <0.000010 128 <0.000010 1290.000002 130 <0.000010 131 <0.000010 132 <0.000010 133 <0.000010 134<0.000010 135 <0.000010 136 <0.000010 137 <0.000010 138 <0.000010 139<0.000010 140 <0.000010 141 <0.000010 142 0.00013 143 <0.000010 144<0.000010 145 <0.000010 146 <0.000010 147 <0.000010 148 <0.000010 149<0.000010 150 <0.000010 151 0.000017 152 <0.000010 153 <0.000010 154<0.000010 155 0.000059 156 <0.000010 157 <0.000010 158 <0.000010 159<0.000010 160 <0.000010 161 <0.000010 162 <0.000010 163 <0.000010 164<0.000010 165 <0.000010 166 <0.000010 167 <0.000010 168 <0.000010 1690.000021 170 0.000022 171 <0.000010 172 <0.000010 173 <0.000010 174<0.000010 175 0.000119 176 0.000023 177 0.000111 178 0.000076 179<0.000010 180 <0.000010 181 0.000017 182 0.000068 183 <0.000010 184<0.000010 185 0.000022 186 0.000047 187 0.00008 188 <0.000010 1890.000018 190 0.000026 191 <0.000010 192 <0.000010 193 <0.000010 194<0.000010 195 <0.000010 196 <0.000010 197 <0.000010 198 <0.000010 199<0.000010 200 <0.000010 201 0.000014 202 <0.000010 203 <0.000010 204<0.000010 205 <0.000010 206 0.000036 207 0.00003 208 0.000104 209<0.000010 210 0.000011 211 0.000058 212 0.0001330 213 <0.000010 214<0.000010 215 <0.000010 216 <0.000010 217 <0.000010 218 0.000013 2190.001192 220 0.000988 221 0.000049 222 0.000938 223 0.000053 224<0.000010 225 0.000196 226 0.000139 227 <0.000010 228 0.026761 2290.002109 230 0.000031 231 0.000770 232 0.001631 233 0.001654 2340.000115 235 0.000023 236 0.000033 237 0.000024 238 <0.000010 2390.000026 240 <0.000010 241 <0.000010 242 0.000057 243 0.000546 2440.000281 245 0.000015 246 0.000144 247 0.000019 248 0.000029 2500.000412 251 0.000571 252 <0.000010 253 0.000052 254 <0.000010 255<0.000010 256 <0.000010 257 0.000052 258 <0.000010 259 <0.000010 2600.000016 261 0.000134 262 <0.000010 263 0.000156 264 0.000036 265<0.000010 266 <0.000010 267 0.000035 268 <0.000010 269 0.000016 270<0.000010 271 0.000039 272 0.000031 273 0.000035 274 0.000040 275<0.000010 276 <0.000010 277 <0.000010 278 0.000252 279 0.000035 2800.000071 281 0.000145 282 <0.000010 283 <0.000010 284 0.000024 285<0.000010 286 <0.000010 287 0.000081 288 0.000251 289 0.000090 290<0.000010 291 <0.000010 292 0.000190 293 0.000093 294 0.000046 295<0.000010 296 0.000512 297 0.000174 298 <0.000010 299 0.000039 3000.001627 301 0.002065 302 0.000332 303 0.000044 304 nd 305 0.000033 3060.002067 307 0.000130 308 0.000141 309 0.000023 310 0.000165 311<0.000010 312 <0.000010 313 0.001102 314 0.000042 315 0.000052 3160.000601 317 <0.000010 318 <0.000010 319 <0.000010 320 <0.000010 321<0.000010 322 <0.000010 323 0.000104 324 <0.000010 325 <0.000010 326<0.000010 327 <0.000010 328 <0.000010 329 0.000030 330 <0.000010 3310.001086 332 0.000621 333 0.000511 334 0.000572 335 0.000150 3360.000198 337 <0.000010 338 0.000013 339 0.000036 340 <0.000010 341<0.000010 342 <0.000010 343 <0.000010 344 <0.000010 345 <0.000010 3460.000042 347 0.000013 348 0.000034 349 0.000023 350 <0.000010 351<0.000010 352 0.000014 353 <0.000010 354 0.000010 355 0.000014 3560.000039 357 <0.000010 358 <0.000010 359 <0.000010 360 <0.000010 361<0.000010 362 0.000016 363 0.000017 364 <0.000010 365 <0.000010 3660.000024 367 nd 368 nd 369 <0.000010 370 0.000285 371 <0.0000010 372 nd373 <0.0000010 374 <0.0000010 375 0.00010999 376 <0.0000010 377<0.0000010 378 <0.0000010 nd = not determinedThe inhibition constant (K_(i)) is the dissociation constant of anenzyme-inhibitor complex or a protein/small molecule complex, whereinthe small molecule is inhibiting binding of one protein to anotherprotein or peptide. So a large K_(i) value indicates a low bindingaffinity and a small K_(i) value indicates a high binding affinity.

TABLE 2 shows inhibition constants for the inhibition of a Bak BH3peptide probe to Bcl-2 protein and indicate that compounds according tothe invention have high binding affinities for anti-apoptotic Bcl-2protein. The compounds are therefore expected to have utility intreatment of diseases during which anti-apoptotic Bcl-2 protein isexpressed.

RS4;11 Cell Viability Assay

The acute lymphoblastic leukemia (ALL) cell line RS4;11 was used as theprimary human cell line to assess the cellular activity of Bcl-2selective agents in vitro and their efficacy in vivo. Previous studieshave shown by BH3 profiling, a mitochondrial assay that classifiesblocks in the intrinsic apoptotic pathway, that RS4;11 cells were highlydependent on BCL-2 for survival and sensitive to the Bcl-2 family memberinhibitor ABT-737 (Blood, 2008, Vol. 111, 2300-2309). The prevalence ofBcl-2 complexed to the proapoptotic BH3 protein Bim in RS4;11 suggeststhat these cells are “primed” or more susceptible to cell death byantagonism of the antiapoptotic protein Bcl-2 for which they depend onfor survival.

RS4;11 cells were cultured in RPMI-1640 supplemented with 2 mML-glutamine, 10% FBS, 1 mM sodium pyruvate, 2 mM HEPES, 1%penicillin/streptomycin (Invitrogen), 4.5 g/L glucose and maintained at37 C containing 5% CO₂. To test for the cellular activity of compoundsin vitro, cells were treated at 50,000 cells per well in 96-wellmicrotiter plates in the presence of 10% human serum for 48 hours in ahumidified chamber with 5% CO₂. Cell cytotoxicity EC₅₀ values wereassessed using CellTiter Glo (Promega) according to the manufacturer'srecommendations. The EC₅₀ values were determined as a percentage ofviable cells following treatment compared to the untreated controlcells.

TABLE 3 RS4; 11 EC₅₀ Values (μM) EXAMPLE # EC50 1 0.712 2 0.783 3 0.01424 0.01854 5 0.01241 6 0.03487 7 0.192 8 0.158 9 0.01476 10 0.05202 110.01393 12 0.03471 13 0.0232 14 3.8947 15 0.01276 16 1.2098 17 0.475 180.086 19 0.465 20 0.191 21 0.062 22 0.085 23 0.045 24 0.00983 25 0.00726 0.05888 27 0.33237 28 0.0419 29 0.02047 30 0.01529 31 0.01565 320.08147 33 0.00711 34 0.00748 35 0.29147 36 0.18137 37 0.00118 38 3.509239 0.01974 40 0.09974 41 0.05801 42 0.53412 43 0.27208 44 0.05309 450.00992 46 >5 47 0.03265 48 0.00333 49 0.35161 50 0.31264 51 0.02308 520.19964 53 0.06674 54 1.9158 55 0.0132 56 0.08654 57 0.42611 58 >5 590.7215 60 0.05948 61 0.18337 62 0.02506 63 0.00751 64 0.00025 65 0.0002566 0.01893 67 0.04954 68 0.10846 69 1.7243 70 >5 71 0.09165 72 0.0075173 0.02369 74 0.057 75 0.01509 76 0.51131 77 0.76196 78 0.01252 790.0649 80 0.06863 81 0.04814 82 0.68383 83 0.197 84 0.158 85 1.95 861.02 87 1.18 88 0.447 89 0.06446 90 0.06299 91 0.18296 92 0.08089 93 >594 1.6946 95 0.02954 96 0.04356 97 0.05557 98 0.0229 99 1.3923 1000.13666 101 0.2991 102 0.62178 103 0.03917 104 0.07125 105 0.05357 1060.82639 107 0.06117 108 0.02407 109 0.18339 110 0.53638 111 0.01451 1120.02063 113 0.00136 114 0.01078 115 0.01184 116 0.02853 117 0.0182 1180.01294 119 0.01138 120 0.00147 121 0.05972 122 0.00185 123 0.00333 1240.21224 125 0.00838 126 0.05359 127 0.00975 128 0.00589 129 0.01484 1300.01059 131 0.01266 132 0.02209 133 0.03186 134 0.00251 135 0.00237 1360.00296 137 0.01272 138 0.00152 139 0.01681 140 0.01275 141 0.02044 1420.34531 143 0.01914 144 0.0212 145 0.004 146 0.01916 147 0.02618 1480.00938 149 0.01347 150 0.05103 151 0.03372 152 0.02037 153 0.01723 1540.02647 155 0.59421 156 0.00805 157 0.01086 158 0.01793 159 0.01179 1600.08363 161 0.03465 162 0.01297 163 0.00432 164 0.01476 165 0.0051 1660.01185 167 0.00093 168 0.08867 169 0.07626 170 0.12515 171 0.05272 1720.02053 173 0.00516 174 0.12621 175 >1 176 0.13353 177 0.15936 1780.20234 179 0.04273 180 0.0118 181 0.10612 182 0.1234 183 0.01753 1840.02323 185 0.02747 186 0.06443 187 0.21494 188 0.01638 189 0.14397 1900.55068 191 0.00691 192 0.00241 193 0.00076 194 0.00819 195 0.00207 1960.00172 197 0.0125 198 0.03619 199 0.00506 200 0.01099 201 0.59132 2020.0438 203 0.02208 204 0.16475 205 0.01059 206 0.05291 207 0.00376 2080.12121 209 0.0045 210 0.06022 211 0.3073 212 0.01283 213 0.0060976 2140.0043751 215 0.00056038 216 0.68263 217 0.0015528 218 0.0072907 219 >1220 >1 221 0.094771 222 >1 223 0.18208 224 0.013887 225 0.56001 2260.1178 227 0.0073566 228 >1 229 >1 230 0.052821 231 0.52301 232 >1233 >1 234 0.13532 235 0.03232 236 0.04292 237 0.05316 238 0.10303 2390.023699 240 0.017266 241 0.11377 242 0.22275 243 0.80718 244 0.79378245 0.083614 246 0.40218 247 0.092976 248 0.099588 250 >1 251 0.91782252 0.003475 253 0.049586 254 0.019908 255 0.009004 256 0.017997 2570.026002 258 0.00055345 259 0.00038795 260 0.0054323 261 0.18366 2620.016346 263 >1 264 0.68866 265 0.0071718 266 0.0072924 267 0.06944 2680.048792 269 0.0072346 270 0.0025216 271 0.43657 272 0.84006 273 0.20925274 0.21418 275 0.14303 276 0.0035006 277 0.0081845 278 0.79393 2790.22492 280 0.45923 281 0.65371 282 0.032187 283 0.013096 284 0.16213285 0.057413 286 0.034464 287 0.59312 288 0.39042 289 0.6687 290 0.10663291 0.016079 292 0.88938 293 0.28715 294 0.12525 295 0.014803 2960.76869 297 0.59157 298 0.070305 299 0.067981 300 0.76334 301 >1 3020.38106 303 0.04776 304 0.29755 305 0.032539 306 0.55348 307 0.12767 3080.257 309 0.052421 310 >1 311 0.035835 312 0.016178 313 >1 314 0.66006315 0.21027 316 >1 317 0.013313 318 0.011566 319 0.0044972 320 0.050974321 0.0188 322 0.012367 323 0.71689 324 0.0045254 325 0.012319 3260.023133 327 0.0027224 328 0.0098808 329 0.42369 330 0.0097843 3310.92638 332 0.45738 333 0.46292 334 >1 335 0.26951 336 0.35134 3370.001759 338 0.003399 339 0.45016 340 0.05646 341 0.031652 342 0.050891343 0.12664 344 0.0066616 345 0.0092536 346 0.19003 347 0.018849 3480.050263 349 0.023086 350 0.0058378 351 0.0020618 352 0.0011961 3530.0050512 354 0.053231 355 0.018771 356 0.026623 357 0.013235 3580.0038131 359 0.0059243 360 0.0098968 361 0.00053755 362 0.031726 3630.02643 364 0.011244 365 0.0030168 366 0.016548 367 nd 368 nd 3690.0079974 370 nd 371 0.007165 372 nd 373 nd 374 0.015475 375 0.56013 3760.008765 377 0.002377 378 0.006764 nd = not determined

TABLE 3 shows the utility of compounds having Formula I to functionallyinhibit anti-apoptotic Bcl-2 protein in a cellular context. The acutelymphoblastic leukemia (ALL) cell line RS4;11 has been shown by BH3profiling, a mitochondrial assay that classifies blocks in the intrinsicapoptotic pathway, to be highly dependent on Bcl-2 for survival and issensitive to the Bcl-2 family member inhibitor ABT-737 (Blood, 2008,Vol. 111, 2300-2309). The ability of compounds to kill RS4;11 cells is adirect measure of the compounds ability to inhibit anti-apoptotic Bcl-2protein function. Compounds of Formula I are very effective in killingRS4;11 cells as demonstrated by low EC₅₀ values.

Compounds taught in U.S. patent application Ser. No. 12/631,404,entitled “BCL-2-SELECTIVE APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OFCANCER AND IMMUNE DISEASES,” filed on Dec. 4, 2009, have utility for thetreatment of various cancers and auto-immune diseases due to theiractivity against Bcl-2 family proteins, and more specifically Bcl-2.These compounds bind to Bcl-2 with high affinity in a FRET based assaydescribed in Ser. No. 12/631,404. The administration of a one or more ofthese compounds to cells that are dependent on Bcl-2 or Bcl-2 familyproteins for survival, such as the RS4:11 B-cell leukemia human tumorcell line, results in apoptosis, also known as programmed cell death.The amount of apoptosis caused by administration of the compound isrepresented by the EC50 in the cell viability assay, which is a measureof the number of living cells after administration of compound.

TABLE 4 identifies certain compounds (described below in Examples in 19,20, 23 and 92 and described more fully in Ser. No. 12/631,404, thedisclosure of which is incorporated herein by reference) with thevarious substituents being defined by R, X and Y as set forth. As can beseen from TABLE 4, these compounds exhibit a trend of increasing bindingaffinity (K_(i)) for Bcl-2 with increasing levels of apoptosis, or celldeath, in the Bcl-2 dependent tumor cell line RS4;11. On this basis, theinventors expect that compounds with even greater affinity towards Bcl-2than those compounds shown in Table 4 will exhibit a similar trend,potentially eliciting even greater levels of apoptosis, whenadministered to cells dependent on Bcl-2 for survival.

TABLE 4 Selected compounds in U.S. patent Application No. 12/631404

Bcl-2 FRET RS4;11 EC50 EXAMPLE R X Y K_(i) (μM) (μM) (23)

C O 0.000083 0.045 (92)

C C 0.000128 0.081 (20)

C C 0.000181 0.191 (19)

C C 0.000226 0.465

To this end, binding affinity and cellular activity for compoundsaccording to the present invention were compared with structurallysimilar indole compounds. In particular, the compounds of the presentinvention, in which a nitrogen is contained at a specific positionwithin the heteroarene fused to the heteroaryl ring were compared withthe corresponding indole compounds, which latter compounds lack only thespecific nitrogen substitution included in the compounds of the presentinvention.

As can be seen in TABLE 5, compounds of the present invention having thespecific nitrogen substitutions shown (i.e., compounds of Examples 1, 2,3, 4, 5, 6, 9, 10, 11, 12, 13, 15, 16, and 17, where Z═N) in factachieve relatively greater levels of apoptosis when administered tocells that depend on Bcl-2 for survival and have increased affinitytowards Bcl-2 relative to the corresponding structural analogs lackingthe specific nitrogen substitution (i.e., compounds of Examples 87, 88,89, 90, 91, 19, 20, 21, 92, 22, 23, 93, and 94, respectively, where Z═C,taught in 9696USL2, the disclosure of which is incorporated herein byreference).

Specifically, the seventh column of TABLE 5 compares binding affinity ofcompounds of the present invention (the compound identified by thedesignated substituents in the uppermost row in each pair of rows setapart by blank rows) to corresponding compounds lacking the describednitrogen substitution. In each comparison, compounds of the presentapplication (upper row of each pair of rows separated by a blank row)bind Bcl-2 with greater affinity to Bcl-2 than the corresponding analogs(lower row of each pair of rows separated by a blank row).

Further, column 8 of TABLE 5 compares the amount of apoptosis in theBcl-2 dependent RS4;11 cell line achieved using compounds of the presentinvention (again the compound identified by the designated substituentsin the uppermost row in each pair of rows set apart by blank rows) tothat achieved using compounds of Examples 87, 88, 89, 90, 91, 19, 20,21, 92, 22, 23, 93, and 94, where Z═C. In each comparison, compounds ofthe present invention (upper row of each pair of rows separated by ablank row) achieve greater extent of apoptosis in Bcl-2 dependent RS4;11cells than the corresponding analogs (lower row of each pair of rowsseparated by a blank row).

The increase in binding affinity between the compounds of the presentinvention and corresponding analogs ranges from 2.7× to greater than100×, and the increased potency in RS4;11 cells ranges from a 1.65×increase to greater than 10× increase.

As detailed below, a specific substitution of a nitrogen atom for acarbon atom leads to unexpected increase in binding affinity toantiapoptotic Bcl-2 and increase in potency in cell viability assaysassessing apoptosis in Bcl-2 dependent cell lines.

This invention therefore comprises a series of compounds thatdemonstrate unexpected properties with respect to their binding to andinhibiting the activity of anti-apoptotic Bcl-2 protein to asignificantly greater extent than corresponding analog compounds.

TABLE 5 Direct comparison of compounds of the present invention withcorresponding analogs.

Bcl-2 FRET RS4;11 EXAMPLE R W X Ring Z ki (μM) EC50 (μM)  (1)

NH NO₂

N 0.000225 0.712 (87)

NH NO₂

C 0.000618 1.180  (2)

NH NO₂

N <0.000010 0.783 (88)

NH NO₂

C 0.672 0.447  (3)

NH NO₂

N 0.000013 0.0142 (89)

NH NO₂

C 0.000074 0.064  (4)

NH NO₂

N <0.00001 0.019 (90)

NH NO₂

C 0.000013 0.063  (5)

NH NO₂

N <0.00001 0.012 (18)

NH NO₂

C 0.000017 0.086  (6)

NH NO₂

N 0.000018 0.035 (91)

NH NO₂

C 0.000487 0.183  (9)

NH NO₂

N <0.00001 0.015 (19)

NH NO₂

C 0.000226 0.465 (10)

NH NO₂

N <0.00001 0.052 (20)

NH NO₂

C 0.000181 0.191 (11)

NH NO₂

N 0.000016 0.014 (21)

NH NO₂

C 0.000912 0.062 (12)

O NO₂

N <0.00001 0.035 (92)

O NO₂

C 0.000128 0.081 (13)

NH NO₂

N <0.00001 0.023 (22)

NH NO₂

C 0.000291 0.085 (15)

NH NO₂

N <0.00001 0.013 (23)

NH NO₂

C 0.000083 0.045 (16)

NH SO₂CF₃

N 0.000219 1.210 (93)

NH SO₂CF₃

C 0.035 >5.000 (17)

NH SO₂CF₃

N 0.000090 0.475 (94)

NH SO₂CF₃

C 0.000678 1.690

More specifically, compounds of the present invention contain asubstitution pattern shown in the diagram below.

Other compounds that contain isomeric ring systems to that shown above,such as those rings systems containing a nitrogen adjacent to theoxygenated carbon within the ring, as shown below, are compromised byinstability.

Specifically, this was discovered by the inventors in the followingcompound preparation. The intermediate structure F, that directlyprecedes the final product of the unstable compound, was preparedaccording to the route below. All intermediates A-F were stable andisolable using techniques known to those skilled in the art.

Intermediate F, shown in the scheme above, was reacted with intermediateG using standard coupling conditions that are known to those skilled inthe art. The reaction mixture was analyzed via HPLC/MS to monitor theformation of a peak corresponding to the compound H. While this peakformed within hours of initiating the reaction below, the peakprogressively disappeared during workup and chromatography, until it nolonger was present. The lack of stability of the putative compoundoriginates from the position of the nitrogen within the fusedring-system described above. This position, which is adjacent to theoxygen-bearing carbon in the 5-substituted-1H-pyrrolo[2,3-c]pyridinering system shown below and described above, makes the compound Hunstable.

It is expected that a compound containing the fused5-substituted-1H-pyrrolo[3,2-b]pyridine ring system below would besimilarly unstable, since the position of the nitrogen is adjacent tothe oxygen-bearing carbon within the ring.

Therefore, compounds with the 5-substituted-1H-pyrrolo[2,3-b]pyridinesare preferred over the isomeric compounds.

It is expected that, because compounds having Formula (I) bind to Bcl-2,they would also have utility as binders to anti-apoptotic proteinshaving close structural homology to Bcl-2, such as, for example,anti-apoptotic Bcl-XL, Bcl-w, Mcl-1 and Bfl-1/A1 proteins.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer spleen cancer, and the like is described in commonly-owned PCT US2004/36770, published as WO 2005/049593, and PCT US 2004/37911,published as WO 2005/024636.

Involvement of Bel-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.

Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.

Involvement of Bel-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

Overexpression of Bel-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem. Cancers include, but are not limited to, hematologic and solidtumor types such as acoustic neuroma, acute leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer (includingestrogen-receptor positive breast cancer), bronchogenic carcinoma,Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, gastric carcinoma, germ cell testicular cancer,gestational trophoblastic disease, glioblastoma, head and neck cancer,heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer,hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lungcancer (including small cell lung cancer and non-small cell lungcancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma,follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma),malignancies and hyperproliferative disorders of the bladder, breast,colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoidmalignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma,oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer,pancreatic cancer, papillary adenocarcinomas, papillary carcinoma,peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostatecancer (including hormone-insensitive (refractory) prostate cancer),rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, testicularcancer (including germ cell testicular cancer), thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer,Wilms' tumor and the like.

It is also expected that compounds having Formula (I) would inhibitgrowth of cells expressing Bcl-2 proteins derived from a pediatriccancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoid/rhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkitt'slymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,inflammatory diseases, and thrombocytopenia, acute or chronic immunedisease associated with organ transplantation, Addison's disease,allergic diseases, alopecia, alopecia areata, atheromatousdisease/arteriosclerosis, atherosclerosis, arthritis (includingosteoarthritis, juvenile chronic arthritis, septic arthritis, Lymearthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoproteinemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglycaemia, autoimmune neutropaenia,autoimmune thrombocytopaenia, autoimmune thyroid disease, B celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transplantation, chronic eosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis, chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,colorectal common varied immunodeficiency (common variablehypogammaglobulinemia), conjunctivitis, connective tissue diseaseassociated interstitial lung disease, contact dermatitis, Coombspositive haemolytic anaemia, cor pulmonale, Creutzfeldt-Jakob disease,cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis,culture negative sepsis, cystic fibrosis, cytokine therapy associateddisorders, Crohn's disease, dementia pugilistica, demyelinatingdiseases, dengue hemorrhagic fever, dermatitis, dermatitis scleroderma,dermatologic conditions, dermatomyositis/polymyositis associated lungdisease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus,Diffuse Lewy body disease, dilated cardiomyopathy, dilated congestivecardiomyopathy, discoid lupus erythematosus, disorders of the basalganglia, disseminated intravascular coagulation, Down's Syndrome inmiddle age, drug-induced interstitial lung disease, drug-inducedhepatitis, drug-induced movement disorders induced by drugs which blockCNS dopamine, receptors, drug sensitivity, eczema, encephalomyelitis,endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis,Epstein-Barr virus infection, erythromelalgia, extrapyramidal andcerebellar disorders, familial hematophagocytic lymphohistiocytosis,fetal thymus implant rejection, Friedreich's ataxia, functionalperipheral arterial disorders, female infertility, fibrosis, fibroticlung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cellarteritis, glomerular nephritis, glomerulonephritides, Goodpasture'ssyndrome, goitrous autoimmune hypothyroidism (Hashimoto's disease),gouty arthritis, graft rejection of any organ or tissue, graft versushost disease, gram negative sepsis, gram positive sepsis, granulomas dueto intracellular organisms, group B streptococci (GBS) infection,Grave's disease, haemosiderosis associated lung disease, hairy cellleukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hayfever, heart transplant rejection, hemochromatosis, hematopoieticmalignancies (leukemia and lymphoma), hemolytic anemia, hemolytic uremicsyndrome/thrombolytic thrombocytopenic purpura, hemorrhage,Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C, HIVinfection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism,Huntington's chorea, hyperkinetic movement disorders, hypersensitivityreactions, hypersensitivity pneumonitis, hyperthyroidism, hypokineticmovement disorders, hypothalamic-pituitary-adrenal axis evaluation,idiopathic Addison's disease, idiopathic leucopenia, idiopathicpulmonary fibrosis, idiopathic thrombocytopaenia, idiosyncratic liverdisease, infantile spinal muscular atrophy, infectious diseases,inflammation of the aorta, inflammatory bowel disease, insulin dependentdiabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/opticneuritis, ischemia-reperfusion injury, ischemic stroke, juvenilepernicious anaemia, juvenile rheumatoid arthritis, juvenile spinalmuscular atrophy, Kaposi's sarcoma, Kawasaki's disease, kidneytransplant rejection, legionella, leishmaniasis, leprosy, lesions of thecorticospinal system, linear IgA disease, lipidemia, liver transplantrejection, Lyme disease, lymphedema, lymphocytic infiltrative lungdisease, malaria, male infertility idiopathic or NOS, malignanthistiocytosis, malignant melanoma, meningitis, meningococcemia,microscopic vasculitis of the kidneys, migraine headache, mitochondrialmultisystem disorder, mixed connective tissue disease, mixed connectivetissue disease associated lung disease, monoclonal gammopathy, multiplemyeloma, multiple systems degenerations (Mencel Dejerine-ThomasShi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease,myasthenia gravis, microscopic vasculitis of the kidneys, Mycobacteriumavium intracellulare, Mycobacterium tuberculosis, myelodysplasticsyndrome, myocardial infarction, myocardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic Imuscular atrophies, neutropenic fever, Non-alcoholic Steatohepatitis,occlusion of the abdominal aorta and its branches, occlusive arterialdisorders, organ transplant rejection, orchitis/epididymitis,orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis,osteoporosis, ovarian failure, pancreas transplant rejection, parasiticdiseases, parathyroid transplant rejection, Parkinson's disease, pelvicinflammatory disease, pemphigus vulgaris, pemphigus foliaceus,pemphigoid, perennial rhinitis, pericardial disease, peripheralatherlosclerotic disease, peripheral vascular disorders, peritonitis,pernicious anemia, phacogenic uveitis, Pneumocystis carinii pneumonia,pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes syndrome), post perfusionsyndrome, post pump syndrome, post-MI cardiotomy syndrome,postinfectious interstitial lung disease, premature ovarian failure,primary biliary cirrhosis, primary sclerosing hepatitis, primarymyxoedema, primary pulmonary hypertension, primary sclerosingcholangitis, primary vasculitis, Progressive supranuclear palsy,psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,pulmonary hypertension secondary to connective tissue disease, pulmonarymanifestation of polyarteritis nodosa, post-inflammatory interstitiallung disease, radiation fibrosis, radiation therapy, Raynaud'sphenomenon and disease, Raynaud's disease, Refsum's disease, regularnarrow QRS tachycardia, Reiter's disease, renal disease NOS,renovascular hypertension, reperfusion injury, restrictivecardiomyopathy, rheumatoid arthritis associated interstitial lungdisease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsissyndrome, septic shock, seronegative arthropathies, shock, sickle cellanemia, Sjögren's disease associated lung disease, Sjögren's syndrome,skin allograft rejection, skin changes syndrome, small bowel transplantrejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinalataxia, spinocerebellar degenerations, spondyloarthopathy, sporadic,polyglandular deficiency type I sporadic, polyglandular deficiency typeII, Still's disease, streptococcal myositis, stroke, structural lesionsof the cerebellum, Subacute sclerosing panencephalitis, sympatheticophthalmia, Syncope, syphilis of the cardiovascular system, systemicanaphylaxis, systemic inflammatory response syndrome, systemic onsetjuvenile rheumatoid arthritis, systemic lupus erythematosus, systemiclupus erythematosus-associated lung disease, systemic sclerosis,systemic sclerosis-associated interstitial lung disease, T-cell or FABALL, Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Th1 Typemediated diseases, thromboangitis obliterans, thrombocytopenia,thyroiditis, toxicity, toxic shock syndrome, transplants,trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibodyhepatitis), type B insulin resistance with acanthosis nigricans, typeIII hypersensitivity reactions, type IV hypersensitivity, ulcerativecolitic arthropathy, ulcerative colitis, unstable angina, uremia,urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins,vasculitis, vasculitic diffuse lung disease, venous diseases, venousthrombosis, ventricular fibrillation, vitiligo acute liver disease,viral and fungal infections, vital encephalitis/aseptic meningitis,vital-associated hemophagocyctic syndrome, Wegener's granulomatosis,Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection ofany organ or tissue, yersinia and salmonella-associated arthropathy andthe like.

Schemes and Experimentals

The following abbreviations have the meanings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄; 9-BBN means9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)-butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane; EDAC HCl means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc meansfluorenylmethoxycarbonyl; HATU means0-(7-azabenzotriazol-1-yl)-N,N′N′N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporous triethylammoniummethylpolystyrene cyanoborohydride; TEA means triethylamine; TFA meanstrifluoroacetic acid; THE means tetrahydrofuran; NCS meansN-chlorosuccinimide; NMM means N-methylmorpholine; NMP meansN-methylpyrrolidine; PPh₃ means triphenylphosphine.

The following schemes are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. Compounds of this invention may bemade by synthetic chemical processes, examples of which are shownherein. It is meant to be understood that the order of the steps in theprocesses may be varied, that reagents, solvents and reaction conditionsmay be substituted for those specifically mentioned, and that vulnerablemoieties may be protected and deprotected, as necessary.

Compounds of Formula (4) can be prepared as shown in SCHEME 1, and canbe used as described in SCHEME 8 to prepare compounds of Formula (I),which are representative of the compounds of the present invention.Compounds of Formula (1) wherein R is alkyl, can be converted tocompounds of Formula (2) using Z³L¹MgX¹, wherein X¹ is a halide, in asolvent such as but not limited to ether or tetrahydrofuran. Compoundsof Formula (3) can be prepared from compounds of Formula (2) using astrong base such as NaH and R⁵⁷X2, wherein X² is a halide and R⁵⁷ is asdescribed herein. Compounds of Formula (3), when treated with aqueousNaOH or LiOH, will provide compounds of Formula (4).

As shown in SCHEME 2, compounds of Formula (5) can be reacted withcompounds of Formula (6) and a reducing agent to provide compounds ofFormula (7). Examples of reducing agents include sodium borohydride,sodium cyanoborohydride, sodium triacetoxyborohydride, polymer supportedcyanoborohydride, and the like. The reaction is typically performed in asolvent such as but not limited to methanol, tetrahydrofuran, anddichloromethane or mixtures thereof. Compounds of Formula (8) can beprepared from compounds of Formula (7) as described in SCHEME 1, and canbe used as described in SCHEME 8 to prepare compounds of Formula (I).

Compounds of Formula (9), when reacted with a compound a Formula (10)wherein X is a halide or triflate, and a base will provide a compound ofFormula (11). Bases useful in the reaction include triethylamine,diisopropylethylamine and the like. Compounds of Formula (13), wherein Yis as described herein for substituents on Z³, can be prepared fromcompounds of Formula (11) and compounds of Formula (12) using Suzukicoupling conditions known to those skilled in the art and readilyavailable in the literature. Compounds of Formula (14) can be preparedfrom compounds of Formula (13) as described in SCHEME 1, and can be usedas described in SCHEME 8 to prepare compounds of Formula (I).

As shown in SCHEME 4, compounds of Formula (17) can be prepared fromcompounds of Formula (15) and compounds of Formula (16), wherein R isalkyl and R³⁸ is as described herein, using Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature. Compounds of Formula (17) can be reduced to compounds ofFormula (18) using a reducing agent such as LiAlH₄ in a solvent such asbut not limited to diethyl ether or THF. Compounds of Formula (19) canbe prepared from compounds of Formula (18) using Dess-Martin periodinaneor Swern oxidation conditions known to those skilled in the art andreadily available in the literature. Compounds of Formula (19) can bereacted with a compound of Formula (5) and a reducing agent to providecompounds of Formula (20). Examples of reducing agents include sodiumborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,polymer supported cyanoborohydride, and the like. The reaction istypically performed in a solvent such as but not limited to methanol,tetrahydrofuran, 1,2-dichloroethane, and dichloromethane or mixturesthereof. Compounds of Formula (21) can be prepared from compounds ofFormula (20) as described in SCHEME 1, and can be used as described inSCHEME 8 to prepare compounds of Formula (I).

As shown in SCHEME 5, compounds of Formula (22), wherein R is alkyl, maybe converted to compounds of Formula (23) by reacting the former,wherein X¹ is C₁, Br, I, or CF₃SO₃—, and compounds of Formula R⁴¹—OH anda catalyst, with or without a first base. Examples of catalysts includecopper(I) trifluoromethanesulfonate toluene complex, PdCl₂, Pd(OAc)₂,and Pd₂(dba)₃. Examples of first bases include triethylamine,N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, and mixtures thereof.

Compounds of Formula (22) may also be converted to compounds of Formula(23) by reacting the former, when X¹ is C₁, F, or NO₂, and compounds ofFormula R⁴¹—OH with a first base. Examples of first bases includetriethylamine, N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, andmixtures thereof.

Compounds of Formula (18) can be reacted with mesyl chloride and a basesuch as but not limited to triethylamine, followed byN-t-butoxycarbonylpiperazine, to provide compounds of Formula (24).Compounds of Formula (25) can be prepared by reacting compounds ofFormula (24) with triethylsilane and trifluoroacetic acid. Compounds ofFormula (25) can be reacted with compounds of Formula (26) and HK₂PO₄ toprovide compounds of Formula (27) in a solvent such as but not limitedto dimethylsulfoxide. Compounds of Formula (28) can be prepared fromcompounds of Formula (27) as described in SCHEME 1, and can be used asdescribed in SCHEME 8 to prepare compounds of Formula (I).

As shown in SCHEME 7, compounds of Formula (1) can be reacted with anappropriate triphenylphosphonium bromide of Formula (29) and a base suchas but not limited to sodium hydride or n-butyllithium to providecompounds of Formula (30). The reaction is typically performed in asolvent such as THF or DMSO. Compounds of Formula (31) can be preparedfrom compounds of Formula (30) as described in SCHEME 1, and can be usedas described in SCHEME 8 to prepare compounds of Formula (I).

As shown in SCHEME 8, compounds of Formula (32), which can be preparedas described herein, may be converted to compounds of Formula (33) byreacting the former with ammonia. Compounds of Formula (33) may beconverted to compounds of Formula (I) by reacting the former andcompounds of Formula (4), (8), (14), (21), (28), (31), or (38) and acoupling agent, with or without a first base. Examples of couplingagents include 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride, 1,1′-carbonyldiimidazole, andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.Examples of first bases include triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

Compounds of Formula (33), prepared as described in SCHEME 8, may alsobe converted to compounds of Formula (I) by reacting the former andcompounds of Formula (34) and a first base. Examples of first basesinclude but are not limited to sodium hydride, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

As shown in SCHEME 10, compounds of Formula (35), wherein L is a bond,alkyl, O, S, S(O), S(O)₂, NH, etc., can be reacted with compounds ofFormula (36), to provide compounds of Formula (37). The reaction istypically performed at elevated temperatures in a solvent such as butnot limited to dimethylsulfoxide, and may require the use of a base suchas but not limited to potassium phosphate, potassium carbonate, and thelike. Compounds of Formula (38) can be prepared from compounds ofFormula (37) as described in SCHEME 1, and can be used as described inSCHEME 8 to prepare compounds of Formula (I).

Compounds of Formula (39), wherein Y is as described herein forsubstituents on Z³, can be prepared from compounds of Formula (39A)wherein X is a halide or triflate, and Y—B(OH)₂ using Suzuki couplingconditions known to those skilled in the art and readily available inthe literature. Compounds of Formula (39) can be reacted with tert-butylpiperazine-1-carboxylate and a reducing agent such as sodiumtriacetoxyborohydride to provide compounds of Formula (40). The reactionis typically performed in a solvent such as but not limited to methylenechloride. Compounds of Formula (41) can be prepared from compounds ofFormula (40) by reacting the latter with R⁵⁷X, wherein X is a halide,and NaH in a solvent such as N,N-dimethylformamide, and then theresulting material can be treated with triethylsilane andtrifluoroacetic acid in dichloromethane. Compounds of Formula (41) canbe used as described in Scheme 10 wherein L¹-Z³ is as shown in Formula(41).

As shown in SCHEME 12, substituted piperazin-2-ones wherein R⁵⁷ isalkyl, can be reacted with compounds of Formula (6) and a reducing agentsuch as sodium triacetoxyborohydride in dichloromethane to providecompounds of Formula (42). Compounds of Formula (42) can be reduced tocompounds of Formula (43) using a reducing agent such as but not limitedto lithium aluminum hydride in a solvent such as but not limited totetrahydrofuran. Compounds of Formula (43) can be used as described inScheme 10 wherein L¹-Z³ is as shown in Formula (43).

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds werenamed using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced ChemistryDevelopment Inc., Toronto, Ontario), ACD/ChemSketch Version 12.01 (13May 2009), Advanced Chemistry Development Inc., Toronto, Ontario), orChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.). Intermediateswere named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.).

Example 14-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 1A tert-butyl4-((4′-chlorobiphenyl-2-yl)methyl)piperazine-1-carboxylate

4′-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butylpiperazine-1-carboxylate (4.23 g), and sodium triacetoxyborohydride(5.61 g) in CH₂Cl₂ (60 mL) were stirred for 24 hours. The reaction wasquenched with methanol and poured into ether. The solution was washedwith water and brine, concentrated, and chromatographed on silica gelwith 2-25% ethyl acetate/hexanes.

Example 1B 1-((4′-chlorobiphenyl-2-yl)methyl)piperazine

EXAMPLE 1A (3.0 g) and triethylsilane (1 mL) were stirred in CH₂Cl₂ (30mL) and trifluoroacetic acid (30 mL) for 2 hours, and the reaction wasconcentrated, and then taken up in ether and concentrated again. Thematerial was taken up in dichloromethane (200 mL) and NaHCO₃ solution(100 mL), and partitioned. The organic layer was dried over Na₂SO₄, andcondensed to give the title compound.

Example 1C tert-butyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-fluorobenzoate

Tert-butyl 4-bromo-2-fluorobenzoate (14.0 g), EXAMPLE 1B (16.05 g),Pd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium(O))(1.40 g),2-(di-tert-butylphosphino)biphenyl (1.82 g), and K₃PO₄ (16.2 g) werestirred in 1,2-dimethoxyethane (300 mL) at 80° C. for 24 hours. Thereaction was cooled and concentrated. The crude product waschromatographed on silica gel with 10-20% ethyl acetate/hexanes.

Example 1D tert-butyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

1H-Pyrrolo[2,3-B]pyridine-5-ol (167 mg), EXAMPLE 1C (500 mg), and Cs₂CO₃(508 mg) were stirred in dimethylsulfoxide (5 mL) at 130° C. for 24hours. The mixture was cooled, diluted with ethyl acetate, washed threetimes with water, and brine, and dried (Na₂SO₄), filtered andconcentrated. The crude product was chromatographed on silica gel with25% ethyl acetate/hexanes.

Example 1E2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 1D (200 mg) and triethylsilane (1 mL) were stirred indichloromethane (15 mL) and trifluoroacetic acid (15 mL) for 1 hour. Themixture was concentrated, taken up in ethyl acetate, washed twice withNaH₂PO₄, and brine, and dried (Na₂SO₄), filtered and concentrated.

Example 1F3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (2.18 g),1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g)were stirred in tetrahydrofuran (30 mL) for 24 hours. The solution wasdiluted with ethyl acetate, washed with NaH₂PO₄ solution and brine, anddried (Na₂SO₄), filtered and concentrated. The product was trituratedfrom ethyl acetate.

Example 1G4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 1E (115 mg), EXAMPLE 1F (67 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (82 mg),and 4-dimethylaminopyridine (26 mg) were stirred in CH₂Cl₂ (3 mL) for 24hours. The reaction was cooled and chromatographed on silica gel with0-5% methanol/ethyl acetate. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.48 (brs, 1H), 8.34 (br s, 1H), 8.31 (m, 1H), 7.90 (d, 1H), 7.68 (m,1H), 7.58 (m, 2H), 7.46 (m, 4H), 7.35 (m, 2H), 7.21 (dd, 1H), 6.76 (m,4H), 6.28 (m, 2H), 3.02 (m, 2H), 2.89 (m, 4H), 2.80 (m, 4H), 2.40 (m,3H), 1.59 (m, 2H), 1.25 (m, 4H), 0.87 (m, 2H).

Example 24-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 2A 4-(3-morpholinopropylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting 3-(N-morpholinyl)-propylaminefor 1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 2B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 2A for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.60 (brs, 1H),8.60 (m, 1H), 8.43 (d, 1H), 7.94 (d, 1H), 7.64 (m, 2H), 7.54 (d, 1H),7.45 (m, 4H), 7.33 (m, 2H), 7.23 (dd, 1H), 6.96 (d, 1H), 6.85 (m, 2H),6.32 (d, 1H), 6.26 (d, 1H), 3.60 (m, 4H), 3.10 (m, 4H), 3.05 (m, 10H),2.40 (m, 2H), 2.33 (m, 2H), 1.77 (m, 2H).

Example 34-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 3A methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoromethanesulfonic anhydride (40 mL) was added. Thereaction mixture was warmed to room temperature and stirred for 24hours. The organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated to give the product.

Example 3B methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 3A (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(O) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether (4×200 mL) was added and the mixturewas filtered. The combined ether solution was concentrated to give theproduct.

Example 3C (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 3B (53.8 g) and ether (400 mL),was added methanol (25 mL) slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted withether (3×100 mL). The extracts were dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with0-30% ethyl acetate/hexanes.

Example 3D tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 3C (29.3 g) andtriethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C., and the mixture wasstirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was added andthe mixture was stirred at room temperature for 24 hours. The suspensionwas washed with brine, dried, (Na₂SO₄), filtered, and concentrated. Thecrude product was chromatographed on silica gel with 10-20% ethylacetate/hexanes.

Example 3E1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

EXAMPLE 3D (1 g) was stirred in dichloromethane (10 mL), trifluoroaceticacid (10 mL), and triethylsilane (1 mL) for 1 hour. The mixture wasconcentrated, taken up in a mixture of dichloromethane (100 mL) andsaturated aqueous Na₂CO₃ solution (20 mL) and stirred for 10 minutes.The layers were separated, and the organic layer was dried over Na₂SO₄,filtered, and concentrated to give the product.

Example 3F 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) intetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide intetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl(triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirredat room temperature for 24 hours. The reaction was diluted with ether,and the resulting solution was washed twice with water. The extractswere dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 10% ethyl acetate/hexanes.

Example 3G 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

To a mixture of EXAMPLE 3F (24.3 g) in tetrahydrofuran (500 mL) at −78°C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5mL) was added, and the mixture was allowed to warm to room temperatureover 1 hour. The reaction was poured into water, extracted three timeswith ethyl acetate, and the combined extracts were washed with brine andconcentrated. The crude product was taken up in tetrahydrofuran (200 mL)at 0° C., and 1M NaOH (69 mL) was added, followed by 30% H₂O₂ (8.43 mL),and the solution was stirred for 1 hour. Na₂S₂O₃ (10 g) was added, andthe pH was adjusted to 4-5 with concentrated HCl and solid NaH₂PO₄. Thesolution was extracted twice with ethyl acetate, and the combinedextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with5-25% ethyl acetate/hexanes.

Example 3H methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate

A mixture of EXAMPLE 3G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The crude product waschromatographed on silica gel with 2-50% ethyl acetate/hexanes.

Example 3I methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of EXAMPLE 3H (1.55 g), EXAMPLE 3E (2.42 g), and HK₂PO₄ (1.42g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24 hours. Thereaction was cooled, diluted with ether (400 mL), and washed with 3×1MNaOH, and brine, and concentrated. The crude product was chromatographedon silica gel with 10-50% ethyl acetate/hexanes.

Example 3J2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 3I (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50° C. wasstirred for 24 hours. The reaction was cooled, added to NaH₂PO₄solution, and extracted three times with ethyl acetate. The combinedextracts were washed with brine, and concentrated to give the pureproduct.

Example 3K tert-butyl1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate

Tert-butyl piperidin-4-ylcarbamate (45.00 g, 225 mmol) anddihydro-2H-pyran-4(3H)-one (24.74 g, 247 mmol) were added todichloromethane (1000 mL). Sodium triacetoxyborohydride (61.90 g, 292mmol) was added, and the solution was stirred at room temperature for 16hours. The solution was extracted with 1M sodium hydroxide and driedover anhydrous sodium sulfate. The solution was filtered andconcentrated and purified by flash column chromatography on silica gelwith 10% methanol (in dichloromethane) increasing to 20% methanol (indichloromethane).

Example 3L 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine dihydrochloride

A solution of EXAMPLE 3K (52.57 g, 185 mmol) in dichloromethane (900 mL)was treated with 4M aqueous HCl (462 mL), and the solution was mixedvigorously at room temperature for 16 hours. Solvent was removed undervacuum to give crude product as the dihydrochloride salt, which was usedwithout further purification.

Example 3M3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)benzenesulfonamide

EXAMPLE 3L (22.12 g, 86 mmol) was added to 1,4-dioxane (300 mL) andwater (43 mL). Triethylamine (43.6 mL, 31.6 g, 313 mmol) was added, andthe mixture was stirred at room temperature until EXAMPLE 3L hadcompletely dissolved. 4-chloro-3-nitrobenzenesulfonamide was added andthe mixture was heated at 90° C. for 16 hours. The mixture was cooled,and the solvents were removed under vacuum. 10% methanol (indichloromethane) was added and the solution was stirred vigorously atroom temperature until a fine suspension was obtained. The solid wasisolated by vacuum filtration and washed with dichloromethane to givepure product.

Example 3N4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E andEXAMPLE 3M for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (brs, 1H), 8.53 (br s, 1H), 8.18 (m, 1H),8.00 (br s, 1H), 7.63 (m, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.12 (m, 1H),7.04 (d, 2H), 6.67 (dd, 1H), 6.37 (d, 1H), 6.20 (d, 1H), 3.95 (m, 2H),3.05 (m, 10H), 2.73 (m, 4H), 2.17 (m, 10H), 1.95 (m, 2H), 1.80 (m, 2H),1.63 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 44-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 4A 4-(1-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting 4-amino-N-methylpiperidine for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 4B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E andEXAMPLE 4A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (brs, 1H), 8.55 (br s, 1H), 8.17 (m, 1H),8.02 (d, 1H), 7.85 (dd, 1H), 7.51 (m, 3H), 7.35 (m, 2H), 7.18 (dd, 1H),7.05 (d, 2H), 6.68 (dd, 1H), 6.38 (d, 1H), 6.20 (d, 1H), 3.90 (m, 1H),3.09 (m, 8H), 2.77 (m, 2H), 2.05-2.30 (m, 10H), 1.95 (s, 3H), 1.39 (t,2H), 1.24 (m, 2H), 0.93 (s, 6H).

Example 54-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 5A3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g),1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) intetrahydrofuran (30 mL) were stirred overnight, neutralized withconcentrated HCl and concentrated. The residue was suspended in ethylacetate and the precipitates were collected, washed with water and driedto provide the title compound.

Example 5B methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoromethanesulfonic anhydride (40 mL) was added. Thereaction mixture was warmed to room temperature and stirred for 24hours. The organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated to give the product.

Example 5C methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 5B (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(O) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether (4×200 mL) was added and the mixturewas filtered. The combined ether solution was concentrated to give theproduct.

Example 5D (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 5C (53.8 g) and ether (400 mL),was added methanol (25 mL) slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted withether (3×100 mL). The extracts were dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with0-30% ethyl acetate/hexanes.

Example 5E tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 5D (29.3 g) andtriethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C., and the mixture wasstirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was added andthe mixture was stirred at room temperature for 24 hours. The suspensionwas washed with brine, dried, (Na₂SO₄), filtered, and concentrated. Thecrude product was chromatographed on silica gel with 10-20% ethylacetate/hexanes.

Example 5F1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

EXAMPLE 5E (200 mg) and triethylsilane (1 mL) were stirred indichloromethane (15 mL) and trifluoroacetic acid (15 mL) for 1 hour. Themixture was concentrated, taken up in ethyl acetate, washed twice withNaH₂PO₄, and brine, and dried (Na₂SO₄), filtered and concentrated.

Example 5G 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) intetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide intetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl(triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirredat room temperature for 24 hours. The reaction was diluted with ether,and the resulting solution was washed twice with water. The extractswere dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 10% ethyl acetate/hexanes.

Example 5H 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

To a mixture of EXAMPLE 5G (24.3 g) in tetrahydrofuran (500 mL) at −78°C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5mL) was added, and the mixture was allowed to warm to room temperatureover 1 hour. The reaction was poured into water, extracted three timeswith ethyl acetate, and the combined extracts were washed with brine andconcentrated. The crude product was taken up in tetrahydrofuran (200 mL)at 0° C., and 1M NaOH (69 mL) was added, followed by 30% H₂O₂ (8.43 mL),and the solution was stirred for 1 hour. Na₂S₂O₃ (10 g) was added, andthe pH was adjusted to 4-5 with concentrated HCl and solid NaH₂PO₄. Thesolution was extracted twice with ethyl acetate, and the combinedextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with5-25% ethyl acetate/hexanes.

Example 5I methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate

A mixture of EXAMPLE 5H (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The crude product waschromatographed on silica gel with 2-50% ethyl acetate/hexanes.

Example 5J methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of EXAMPLE 5I (1.55 g), EXAMPLE 5F (2.42 g), and HK₂PO₄ (1.42g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24 hours. Thereaction was cooled, diluted with ether (400 mL), and washed with 3×1MNaOH, and brine, and concentrated. The crude product was chromatographedon silica gel with 10-50% ethyl acetate/hexanes.

Example 5K2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 5J (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50° C. wasstirred for 24 hours. The reaction was cooled, added to NaH₂PO₄solution, and extracted three times with ethyl acetate. The combinedextracts were washed with brine, and concentrated to give the pureproduct.

Example 5L4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 5K (3.39 g), EXAMPLE 5A (1.87 g),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.39 g),and 4-dimethylaminopyridine (1.09 g) were stirred in CH₂Cl₂ (40 mL) for24 hours. The reaction was cooled and chromatographed on silica gel with25-100% ethyl acetate/hexanes, then 10% methanol/ethyl acetate with 1%acetic acid, to give the product (1.62 g, 32%) as a white solid. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) 11.65 (br s, 1H), 8.55 (br s, 1H), 8.04(d, 1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04(d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30(m, 4H), 3.07 (m, 4H), 2.73 (m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61(dd, 2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).

Example 64-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 6A 4-(4-methylpiperazin-1-ylamino)-3-nitrobenzenesulfonamide

A 50 mL round-bottomed flask was charged with4-chloro-3-nitrobenzenesulfonamide (1 g, 4.23 mmol),4-methylpiperazin-1-amine dihydrochloride (1 g, 5.32 mmol), andN¹,N¹,N²,N²-tetramethylethane-1,2-diamine (3 mL, 20.01 mmol) in dioxane(10 mL). The reaction mixture was refluxed for 12 hours. After thistime, the reaction mixture was cooled to room temperature, the saltfiltered off via a Buchner funnel, and the solvent removed in vacuo. Thecrude product was added to a silica gel column (Analogix, SF65-200 g)and purified by eluting with 0-5% methanol in dichloromethane.

Example 6B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E andEXAMPLE 6A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (brs, 1H), 9.09 (br s, 1H), 8.47 (d, 1H),8.24 (dd, 1H), 7.99 (d, 1H), 7.50 (m, 4H), 7.34 (d, 2H), 7.04 (d, 2H),6.64 (dd, 1H), 6.35 (d, 1H), 6.20 (d, 1H), 3.04 (m, 4H), 2.89 (m, 4H),2.73 (m, 2H), 2.34 (s, 3H), 2.17 (m, 6H), 1.95 (br s, 2H), 1.38 (t, 2H),1.05 (m, 4H), 0.93 (s, 6H).

Example 72-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 7A ethyl 2-(9H-carbazol-4-yloxy)-4-fluorobenzoate

This EXAMPLE was prepared by substituting ethyl 2,4-difluorobenzoate formethyl 2,4-difluorobenzoate and 4-hydroxycarbazole for EXAMPLE 3G inEXAMPLE 3H.

Example 7B ethyl2-(9H-carbazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This EXAMPLE was prepared by substituting EXAMPLE 7A for EXAMPLE 3H inEXAMPLE 3I.

Example 7C2-(9H-carbazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 7B for EXAMPLE 3I inEXAMPLE 3J, except here upon completion of the reaction, water and 2NHCl were added to adjust the pH to 2, and the HCl salt of the productwas extracted using CHCl₃/CH₃OH.

Example 7D2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 7C for EXAMPLE 1E andEXAMPLE 4A for EXAMPLE 1F in EXAMPLE 1G, except here the purificationwas done by preparative HPLC using a C18 column, 250×50 mm, 10μ, andeluting with a gradient of 20-100% CH₃CN vs. 0.1% trifluoroacetic acidin water, giving the product as a bistrifluoroacetate salt. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.82 (br s, 1H), 11.40 (s, 1H), 9.70, 9.40(both v br s, total 2H), 8.40 (d, 1H), 8.10 (br d, 1H), 7.90 (br d, 1H),7.72 (dd, 1H), 7.60 (d, 1H), 7.48 (d, 1H), 7.38 (m, 3H), 7.22 (m, 2H),7.07 (m, 4H), 6.78 (dd, 1H), 6.43 (dd, 1H), 6.19 (s, 1H), 3.97 (m, 1H),3.80 (m, 2H), 3.60, 3.30, 3.10, 2.80 (all br m, total 11H), 2.20, 2.10,2.00 (all br m, total 8H), 1.78 (m, 2H), 1.42 (m, 2H), 1.25 (m, 2H),0.92 (s, 6H).

Example 82-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 8A 3-nitro-4-(3-(pyrrolidin-1-yl)propylamino)benzenesulfonamide

This EXAMPLE was prepared by substituting3-(pyrrolidin-1-yl)propan-1-amine for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 8B2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 7C for EXAMPLE 1E andEXAMPLE 8A for EXAMPLE 1F in EXAMPLE 1G, except here the purificationwas done by preparative HPLC using a C18 column, 250×50 mm, 10μ, andeluting with a gradient of 20-100% CH₃CN vs. 0.1% trifluoroacetic acidin water, giving the product as a bistrifluoroacetate salt. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.80 (br s, 1H), 11.42 (s, 1H), 9.50, 9.25(both v br s, total 2H), 8.58 (br t, 1H), 8.43 (d, 1H), 7.91 (d, 1H),7.72 (dd, 1H), 7.60 (d, 1H), 7.50 (d, 1H), 7.38 (m, 3H), 7.23 (m, 2H),7.07 (m, 3H), 6.93 (d, 1H), 6.78 (dd, 1H), 6.44 (dd, 1H), 6.18 (s, 1H),3.70, 3.60, 3.20. 3.00 (all br m, total 18H), 2.18 (br m, 2H), 2.00-180(envelope, 8H), 1.42 (m, 2H), 0.92 (s, 6H).

Example 9Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 9A Trans-tert-butyl 4-morpholinocyclohexylcarbamate

A solution of tert-butyl-4-aminocyclohexylcarbamate (20.32 g, 95 mmol),bis(2-bromoethyl) ether (14.30 ml, 114 mmol) and triethylamine (33.0 ml,237 mmol) in N,N-dimethylformamide (200 ml) was stirred for 16 hours at70° C. The reaction mixture was cooled down to room temperature,concentrated and the product was extracted with ethyl acetate. Theorganic layer was washed with sodium carbonate solution (15% aq.), driedand concentrated. The product was used in next step withoutpurification.

Example 9B Trans-4-morpholinocyclohexanamine dihydrochloride

To a solution of trans-tert-butyl-4-morpholinocyclohexylcarbamate (19.2g, 67.5 mmol) in dichloromethane (100 ml) was added HCl (100 ml, 400mmol) (4M in dioxane) and the reaction mixture was stirred for 16 hoursat room temperature. The reaction mixture was diluted with ether andsolid salt was filtered off, and dried in an oven.

Example 9CTrans-4-(4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide

A solution of trans-4-morpholinocyclohexanamine dihydrochloride (5 g,19.44 mmol), 4-fluoro-3-nitrobenzenesulfonamide (4.32 g, 19.63 mmol) andtriethylamine (20 ml, 143 mmol) in tetrahydrofuran (60 ml) was stirredfor 16 hours at room temperature. The solid product was filtered off,washed with tetrahydrofuran, ether, dichloromethane (3×) and dried undervacuum.

Example 9DTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E andEXAMPLE 9C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.61 (brs, 1H), 8.49 (br s, 1H), 8.12 (m, 1H),7.99 (br s, 1H), 7.71 (m, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.04 (d, 2H),7.01 (m, 1H), 6.65 (dd, 1H), 6.36 (d, 1H), 6.21 (d, 1H), 3.60 (m, 4H),3.04 (m, 4H), 2.73 (m, 2H), 2.57 (m, 2H), 2.42 (m, 1H), 2.18 (m, 6H),2.05 (m, 2H), 1.95 (m, 2H), 1.90 (m, 2H), 1.38 (m, 6H), 1.15 (m, 3H),0.92 (s, 6H).

Example 104-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 10A 4-(2-methoxyethylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting 2-methoxyethylamine for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 10B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E andEXAMPLE 10A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (brs, 1H), 8.58-8.49 (m, 1H), 8.55 (d,1H), 8.03 (d, 1H), 7.79 (m, 1H), 7.49 (m, 3H), 7.34 (m, 2H), 7.06 (m,1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 3.61-3.51(m, 4H), 3.31 (s, 3H), 3.07 (m, 4H), 2.74 (m, 2H), 2.17 (m, 6H), 1.95(br s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 114-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 11A(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamideand(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide

This EXAMPLE was prepared by substituting(tetrahydro-2H-pyran-3-yl)methanamine for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 11B(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide

The racemic mixture of EXAMPLE 11A was resolved by chiral SFC on an ADcolumn (21 mm i.d.x 250 mm in length) using a gradient of 10-30% 0.1%diethylamine methanol in CO₂ over 15 minutes (oven temperature: 40° C.;flow rate: 40 mL/minute) to provide the title compound.

Example 11C(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide

The racemic mixture of EXAMPLE 11A was resolved by chiral SFC on an ADcolumn (21 mm i.d.x 250 mm in length) using a gradient of 10-30% 0.1%diethylamine methanol in CO₂ over 15 minutes (oven temperature: 40° C.;flow rate: 40 mL/minute) to provide the title compound.

Example 11D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a mixture of EXAMPLE 3J (59.8 mg, 0.105 mmol), EXAMPLE 11B (33 mg,0.105 mmol) and N,N-dimethylpyridin-4-amine (38.4 mg, 0.314 mmol) indichloromethane (5 ml) was added1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (24.07mg, 0.13 mmol). The reaction mixture was stirred at room temperatureovernight and concentrated. The residue was purified by reverse phaseHPLC on a C18 column using a gradient of 40-60% acetonitrile/0.1%trifluoroacetic acid in water to give the title compound as thetrifluoroacetate salt. The trifluoroacetic acid salt was dissolved indichloromethane (6 ml) and washed with 50% aqueous NaHCO₃. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated to give the titlecompound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 11.40(s, br, 1H), 8.53-8.58 (m, 2H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.47-7.54(m, 3H), 7.34 (d, 2H), 7.02-7.09 (m, 3H), 6.67 (dd, 1H), 6.39 (dd, 1H),6.19 (d, 1H), 3.79 (dd, 1H), 3.69-3.73 (m, 1H), 3.22-3.37 (m, 3H),3.16-3.21 (m, 1H), 3.07 (s, 4H), 2.74 (s, 2H), 2.09-2.24 (m, 6H), 1.95(s, 2H), 1.86-1.93 (m, 1H), 1.79-1.85 (m, 1H), 1.58-1.64 (m, 1H),1.42-1.51 (m, 1H), 1.38 (t, 2H), 1.25-1.34 (m, 1H), 0.92 (s, 6H).

Example 124-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 12A 4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide

(1,4-Dioxan-2-yl)methanol (380 mg, 3.22 mmol) in tetrahydrofuran (30 ml)was treated with sodium hydride (60%) (245 mg, 6.13 mmol) at roomtemperature for 30 minutes. The reaction mixture was cooled in an icebath and 4-fluoro-3-nitrobenzenesulfonamide (675 mg, 3.06 mmol) wasadded. The resulting mixture was stirred at room temperature for 2 hoursand another portion of sodium hydride (60%) (245 mg, 6.13 mmol) wasadded. The reaction mixture was stirred overnight and quenched with icewater (3 ml). The cloudy mixture was filtered and the filtrate wasconcentrated. The residue was triturated with methanol to give the titlecompound.

Example 12B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 12A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.42 (s, br, 1H), 8.34 (s, 1H),8.03 (d, 2H), 7.48-7.55 (m, 3H), 7.41 (d, 1H), 7.35 (d, 2H), 7.04 (d,2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.21 (d, 1H), 4.20-4.28 (m, 2H),3.85-3.91 (m, 1H), 3.82 (dd, 1H), 3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H),3.41-3.51 (m, 2H), 3.05-3.17 (m, 4H), 2.83 (s, br, 2H), 2.27 (s, br,4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 134-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 11C in place of EXAMPLE 11B. The proton NMR spectra of EXAMPLE13 and EXAMPLE 11D are identical. ¹H NMR (500 MHz, dimethylsulfoxide-d₆)δ 11.68 (s, 1H), 11.40 (s, br, 1H), 8.53-8.58 (m, 2H), 8.04 (d, 1H),7.80 (dd, 1H), 7.47-7.54 (m, 3H), 7.34 (d, 2H), 7.02-7.09 (m, 3H), 6.67(dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.79 (dd, 1H), 3.69-3.73 (m, 1H),3.22-3.37 (m, 3H), 3.16-3.21 (m, 1H), 3.07 (s, 4H), 2.74 (s, 2H),2.09-2.24 (m, 6H), 1.95 (s, 2H), 1.86-1.93 (m, 1H), 1.79-1.85 (m, 1H),1.58-1.64 (m, 1H), 1.42-1.51 (m, 1H), 1.38 (t, 2H), 1.25-1.34 (m, 1H),0.92 (s, 6H).

Example 144-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(2-naphthylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingnaphthalene-2-sulfonamide (47 mg, 0.227 mmol) in place of EXAMPLE 11B.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.82 (s, 1H), 11.69 (s, 1H),8.51 (s, 1H), 8.08 (d, 1H), 8.05 (d, 1H), 7.97 (dd, 2H), 7.82 (dd, 1H),7.66-7.71 (m, 1H), 7.63 (t, 1H), 7.54 (d, 1H), 7.47-7.52 (m, 2H), 7.34(d, 2H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.39 (dd, 1H), 6.18 (s, 1H), 3.04(s, 4H), 2.72 (s, 2H), 2.10-2.20 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H),0.92 (s, 6H).

Example 154-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 15A methyl 6,6-dimethyl-4-oxotetrahydro-2H-pyran-3-carboxylate

To a suspension of hexane-washed NaH (0.72 g, 60% in mineral oil) intetrahydrofuran (30 mL) was added a solution of2,2-dimethyldihydro-2H-pyran-4(3H)-one (2.0 g) in tetrahydrofuran (20mL). The suspension was stirred at room temperature for 30 minutes. Thedimethylcarbonate (6.31 mL) was added dropwise by syringe. The mixturewas heated to reflux for 4 h. LC/MS showed the expected product as themajor product. The mixture was acidified with 5% HCl and extracted withdichloromethane (100 mL×3) and washed with water, brine and dried overNa₂SO₄. After evaporation, the crude product was loaded on a column andeluted with 10% ethyl acetate in hexane to give the product.

Example 15B methyl6,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydro-2H-pyran-3-carboxylate

To a cooled (0° C.) stirring suspension of NaH (0.983 g, 60% in mineraloil) in ether (50 mL) was added EXAMPLE 15A (3.2 g). The mixture wasstirred at 0° C. for 30 minutes before the addition of Tf₂O (4.2 mL).The mixture was then stirred at room temperature overnight. The mixturewas diluted with ether (200 mL) and washed with 5% HCl, water and brine.After drying over Na₂SO₄, evaporation of solvent gave the crude productwhich was used in the next step without further purification.

Example 15C methyl4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylate

To a solution of EXAMPLE 15B (2.88 g), 4-chlorophenylboronic acid (1.88g) and Pd(Ph₃P)₄ (0.578 g) in toluene (40 mL) and ethanol (10 mL) wasadded 2N Na₂CO₃ (10 mL). The mixture was stirred at reflux overnight.The mixture was diluted ether (300 mL) and washed with water, brine anddried over Na₂SO₄. After evaporation of solvent, the residue was loadedon a column and eluted with 3% ethyl acetate in hexane to give theproduct.

Example 15D(4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methanol

To a solution of EXAMPLE 15C (1.6 g) in ether (20 mL) was added LiAlH₄(1.2 g). The mixture was stirred for 4 hours. The mixture was acidifiedcarefully with 5% HCl and extracted with ethyl acetate (100 mL×3) andwashed with water, brine and dried over Na₂SO₄. After concentration, thecrude product was loaded on a column and eluted with 10% ethyl acetatein hexane to give the product.

Example 15E4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carbaldehyde

To a solution of oxalyl chloride (1.1 g) in dichloromethane (30 mL) at−78° C. was added dimethylsulfoxide (6.12 mL). The mixture was stirredat the temperature for 30 minutes, and then a solution of EXAMPLE 15D(1.2 g) in dichloromethane (10 mL) was added. The mixture was stirred at−78° C. for 2 hours before the addition of triethylamine (10 mL). Themixture was stirred overnight and the temperature was allowed to rise toroom temperature. The mixture was diluted with ether (300 mL) and washedwith water, brine and dried over Na₂SO₄. Concentration of the solventand column purification (5% ethyl acetate in hexane) gave the product.

Example 15F methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(piperazin-1-yl)benzoate

A mixture of EXAMPLE 3H (20.5 g) and piperazine (37.0 g) indimethylsulfoxide (200 mL) was heated to 110° C. for 24 hours, and themixture was allowed to cool to room temperature. The mixture was pouredinto water (1 L), extracted three times with dichloromethane, and thecombined extracts were washed with 2× water, and brine and filtered andconcentrated to give the pure product.

Example 15G methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 15E (100 mg) and EXAMPLE 15F (177 mg) indichloromethane (10 mL) was added sodium triacetoxyborohydride (154 mg).The mixture was stirred overnight. The mixture was diluted with ethylacetate (200 mL) and washed with 2% NaOH, water and brine. After dryingover Na₂SO₄, the mixture was filtered and the solvent was evaporatedunder vacuum. The residue was loaded on a column and eluted with 30%ethyl acetate in hexane to give the pure product.

Example 15H2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 15G (254 mg) in tetrahydrofuran (4 mL),methanol (2 mL) and water (2 mL) was added LiOH H₂O (126 mg). Themixture was stirred overnight. The mixture was then neutralized with 5%HCl and diluted with ethyl acetate (200 mL). After washing with brine,it was dried over Na₂SO₄. Filtration and evaporation of solvent gave theproduct.

Example 1514-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G, substitutingEXAMPLE 1E with EXAMPLE 15H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.68 (br s, 1H), 11.42 (s, 1H), 8.60 (m, 1H), 8.57 (d, 1H), 8.05 (d,1H), 7.80 (dd, 1H), 7.48-7.54 (m, 3H), 7.38 (d, 2H), 7.12 (m, 3H), 6.68(dd, 1H), 6.40 (dd, 1H), 6.20 (s, 1H), 4.11 (s, 2H), 3.85 (m, 2H), 3.27(m, 6H), 3.07 (m, 2H), 2.84 (m, 2H), 2.14 (m, 5H), 1.92 (m, 1H), 1.42(m, 2H), 1.24 (m, 2H), 1.10 (s, 6H).

Example 164-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 16A4-(2-methoxyethylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.536 g, 5mmol), 2-methoxyethanamine (0.376 g, 5 mmol), and triethylamine (1.939g, 15 mmol) in anhydrous tetrahydrofuran (30 mL) solution was heated at55° C. for 3 hours. The solution was diluted with ethyl acetate, washedwith water and brine, and dried (Na₂SO₄), filtered and the filtrate wasconcentrated. The crude material was used in the next step withoutfurther purification.

Example 16B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E andEXAMPLE 16A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.67 (brs, 1H), 8.14 (m 1H), 8.03 (d, 1H), 7.91(d, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.19 (s, 1H), 7.04 (m, 3H), 6.67(dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 3.51 (m, 4H), 3.28 (s, 3H), 3.06(m, 4H), 2.75 (m, 2H), 2.17 (m, 6H), 1.95 (m, 2H), 1.39 (t, 2H), 0.93(s, 6H).

Example 174-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 17A4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This EXAMPLE was prepared by substituting1-(tetrahydropyran-4-yl)methylamine for 2-methoxyethanamine in EXAMPLE16A.

Example 17B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 3J for EXAMPLE 1E andEXAMPLE 17A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.70 (brs, 1H), 8.15 (m 1H), 8.04 (d, 1H), 7.92(d, 1H), 7.51 (m, 3H), 7.34 (d, 2H), 7.19 (s, 1H), 7.05 (m, 3H), 6.68(dd, 1H), 6.40 (m, 1H), 6.18 (d, 1H), 3.85 (m, 2H), 3.25 (m, 4H), 3.07(m, 4H), 2.77 (m, 2H), 2.17 (m, 6H), 1.95 (m, 2H), 1.84 (m, 1H), 1.54(m, 2H), 1.39 (t, 2H), 1.24 (m, 2H), 0.93 (s, 6H).

Example 184-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 18A methyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate

A mixture of 5-hydroxyindole (8.5 g), methyl 2,4-difluorobenzoate (7.05g), and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The crude product waschromatographed on silica gel with 2-50% ethyl acetate/hexanes.

Example 18B methyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of EXAMPLE 18A (1.7 g), EXAMPLE 3E (1.8 g), and HK₂PO₄ (1.21g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24 hours. Thereaction was cooled, diluted with ether (400 mL), and washed with 3×1MNaOH, and brine, and concentrated. The crude product was chromatographedon silica gel with 10-50% ethyl acetate/hexanes.

Example 18C2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 18B (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50° C. wasstirred for 24 hours. The reaction was cooled, added to NaH₂PO₄solution, and extracted three times with ethyl acetate. The combinedextracts were washed with brine, and concentrated to give the pureproduct.

Example 18D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 11D by replacingEXAMPLE 3J with EXAMPLE 18C, and EXAMPLE 1F for EXAMPLE 11B. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.18 (s, 2H), 8.59-8.64 (m, 2H), 7.80 (dd,1H), 7.52 (d, 1H), 7.39-7.42 (m, 2H), 7.33 (d, 2H), 7.16 (d, 1H), 7.10(d, 1H), 7.03 (d, 2H), 6.8 (dd, 1H), 6.65 (dd, 1H), 6.40)s, 1H), 6.14(d, 1H), 3.85 (dd, 2H), 3.24-3.32 (m, 4H), 3.03 (s, 3H), 2.73 (s, 2H),2.12-2.17 (m, 5H), 1.68-1.94 (m, 3H), 1.61 (d, 2H), 1.37 (t, 2H),1.24-1.27 (m, 2H), 0.92 (s, 6H).

Example 19Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 11D by replacingEXAMPLE 11B with EXAMPLE 9B and EXAMPLE 3J with EXAMPLE 18C. ¹H NMR (500MHz, pyridine-d₅) δ 12.29 (s, 1H), 9.29 (d, J=2.1 Hz, 1H), 8.37 (d,J=7.6 Hz, 1H), 8.32 (dd, J=9.3, 2.3 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H),7.52-7.57 (m, 2H), 7.39-7.47 (m, 3H), 7.10 (dd, J=8.7, 2.3 Hz, 1H),7.05-7.08 (m, 2H), 6.90 (d, J=9.5 Hz, 1H), 6.74 (dd, J=9.0, 2.3 Hz, 1H),6.59-6.63 (m, 1H), 6.55 (d, J=2.4 Hz, 1H), 3.72-3.78 (m, 4H), 3.33-3.43(m, 1H), 2.99-3.09 (m, 4H), 2.76 (s, 2H), 2.46-2.54 (m, 4H), 2.16-2.29(m, 3H), 2.09-2.14 (m, 4H), 2.05 (d, J=11.9 Hz, 2H), 1.97 (d, J=1.8 Hz,2H), 1.87 (d, J=11.6 Hz, 2H), 1.19-1.42 (m, 6H), 0.93 (s, 6H).

Example 204-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 11D by replacingEXAMPLE 11B with EXAMPLE 10A and EXAMPLE 3J with EXAMPLE 18C. ¹H NMR(400 MHz, dimethylsulfoxide-d₆) δ 11.20 (br. s, 1H) 11.15 (s, 1H) 8.59(m, 2H) 7.81 (dd, 1H) 7.50 (d, 1H) 7.36 (m, 4H) 7.08 (m, 4H) 6.85 (dd,1H) 6.65 (dd, 1H) 6.38 (m, 1H) 6.14 (m, 1H) 3.58 (m, 4H) 3.30 (s, 3H)3.03 (m, 4H) 2.73 (s, 2H) 2.15 (m, 6H) 1.96 (s, 2H) 1.38 (t, 2H) 0.92(s, 6H)

Example 214-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared as described in EXAMPLE 11D by replacingEXAMPLE 3J with EXAMPLE 18C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ11.17 (s, 2H), 8.53-8.65 (m, 2H), 7.80 (d, 1H), 7.51 (d, 1H), 7.38-7.44(m, 2H), 7.33 (d, 2H), 7.15 (s, 1H), 7.02-7.09 (m, 3H), 6.82-6.92 (m,1H), 6.65 (d, 1H), 6.39 (s, 1H), 6.14 (s, 1H), 3.68-3.82 (m, 2H),3.22-3.32 (m, 2H), 3.13-3.22 (m, 1H), 3.03 (s, 4H), 2.72 (s, 2H),2.09-2.23 (m, 6H), 1.78-1.98 (m, 4H), 1.56-1.66 (m, 1H), 1.43-1.51 (m,1H), 1.37 (t, 2H), 1.22-1.33 (m, 1H), 0.92 (s, 6H).

Example 224-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 11C in place of EXAMPLE 11B, and EXAMPLE 18C in place of EXAMPLE3J. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H), 8.53-8.65(m, 2H), 7.80 (d, 1H), 7.51 (d, 1H), 7.38-7.44 (m, 2H), 7.33 (d, 2H),7.15 (s, 1H), 7.02-7.09 (m, 3H), 6.82-6.92 (m, 1H), 6.65 (d, 1H), 6.39(s, 1H), 6.14 (s, 1H), 3.68-3.82 (m, 2H), 3.22-3.32 (m, 2H), 3.13-3.22(m, 1H), 3.03 (s, 4H), 2.72 (s, 2H), 2.09-2.23 (m, 6H), 1.78-1.98 (m,4H), 1.56-1.66 (m, 1H), 1.43-1.51 (m, 1H), 1.37 (t, 2H), 1.22-1.33 (m,1H), 0.92 (s, 6H).

Example 234-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 23A methyl 2-(1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 15F by replacingEXAMPLE 3H with EXAMPLE 18A.

Example 23B methyl2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 15G by replacingEXAMPLE 15F with EXAMPLE 23A.

Example 23C2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 15H by replacingEXAMPLE 15G with EXAMPLE 23B.

Example 23D4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 11D by replacingEXAMPLE 11B with EXAMPLE 1F, and EXAMPLE 3J with EXAMPLE 23C. ¹H NMR(400 MHz, dimethylsulfoxide-d₆) δ 11.20 (br s, 1H), 11.17 (s, 1H), 8.63(t, 1H), 8.59 (d, 1H), 7.79 (dd, 1H), 7.51 (d, 1H), 7.36 (m, 3H), 7.13(m, 2H), 6.86 (dd, 1H), 6.66 (dd, 1H), 6.39 (s, 1H), 6.15 (d, 1H), 4.10(s, 2H), 3.85 (m, 3H), 3.50 (m, 2H), 3.42 (m, 2H), 3.24 (m, 4H), 3.02(m, 4H), 2.82 (m, 2H), 2.16 (m, 2H), 1.61 (m, 3H), 1.25 (m, 4H), 1.17(s, 6H).

Example 244-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 24A3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

(Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20 mL)was treated with 60% NaH (1.377 g). The solution was stirred for 20minutes at the room temperature. To this solution was added4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-wise. The reactionwas stirred for another 2 hours. The mixture was poured into water,neutralized with 10% HCl, and extracted with ethyl acetate three times.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified with flash columnchromatography on silica gel eluting with 20-60% ethyl acetate inhexanes.

Example 24B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 24A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.33 (s, 1H), 8.00-8.02 (m, 2H), 7.50-7.53 (m, 3H), 7.34-7.36 (m,3H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (d, 1H), 6.21 (s, 1H), 4.06 (d,2H), 3.88 (dd, 2H), 3.08 (s, 4H), 2.80 (s, 2H), 2.25 (s, 4H), 2.15 (s,2H), 1.96 (s, 2H), 1.63-1.66 (m, 2H), 1.52-1.55 (m, 1H), 1.33-1.40 (m,4H), 0.92 (s, 6H).

Example 254-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 25A 4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 1F using(1,4-dioxan-2-yl)methanamine in place of(tetrahydropyran-4-yl)methanamine.

Example 25B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 25A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 11.38 (s, 1H), 8.53-8.59 (m, 2H),8.03 (d, 1H), 7.81 (dd, 1H), 7.46-7.54 (m, 3H), 7.34 (d, 2H), 7.09 (d,1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H), 6.19 (d, 1H), 3.75-3.86(m, 3H), 3.58-3.68 (m, 2H), 3.45-3.52 (m, 2H), 3.35-3.43 (m, 2H), 3.07(s, 4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92(s, 6H)

Example 264-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 26A 3-nitro-4-(2,2,2-trifluoroethylamino)benzenesulfonamide

The title compound was prepared by substituting2,2,2-trifluoroethanamine for (tetrahydropyran-4-yl)methylamine inEXAMPLE 1F.

Example 26B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.48 (s,1H), 8.40 (m, 2H), 7.90 (d, 1H), 7.71 (dd, 1H), 7.59 (d, 1H), 7.40 (t,1H), 7.34 (d, 2H), 7.25 (d, 1H), 7.06 (m, 3H), 6.61 (dd, 1H), 6.26 (m,2H), 4.32 (m, 2H), 3.00 (m, 4H), 2.73 (s, 2H), 2.19 (m, 6H), 1.96 (s,2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 274-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 27A 3-nitro-4-(3,3,3-trifluoropropylamino)benzenesulfonamide

The title compound was prepared by substituting3,3,3-trifluoropropan-1-amine for (tetrahydropyran-4-yl)methylamine inEXAMPLE 1F.

Example 27B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 27A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.47 (s,1H), 8.37 (d, 1H), 8.29 (m, 1H), 7.89 (d, 1H), 7.61 (m, 2H), 7.39 (t,1H), 7.35 (d, 2H), 7.22 (d, 1H), 7.05 (d, 2H), 6.75 (d, 1H), 6.62 (dd,1H), 6.27 (m, 2H), 3.59 (q, 2H), 3.00 (m, 4H), 2.73 (s, 2H), 2.66 (m,2H), 2.18 (m, 6H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (m, 6H).

Example 284-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 28A (S)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide

The racemic mixture of EXAMPLE 12A was resolved on a SFC chiral ADcolumn to provide the title compound.

Example 28B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 28A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 2H), 8.35 (s, 1H), 8.03 (d, 2H),7.48-7.57 (m, 3H), 7.42 (d, 1H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd,1H), 6.39 (dd, 1H), 6.21 (s, 1H), 4.19-4.30 (m, 2H), 3.85-3.92 (m, 1H),3.73-3.85 (m, 2H), 3.58-3.70 (m, 2H), 3.40-3.52 (m, 2H), 3.10 (s, 4H),2.85 (s, 2H), 2.18-2.39 (m, 3H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t,2H), 0.93 (s, 6H).

Example 29Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 29ACis-4-((4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and EXAMPLE 34A (1 g) intetrahydrofuran (20 mL) was treated with N,N-diisopropylethylamine(0.871 mL) overnight. The reaction mixture was concentrated and theresidue was purified by reverse phase chromatography, eluted with 40-55%acetonitrile in 0.1% trifluoroacetic acid in water over min to give thecis isomer EXAMPLE 29A and trans isomer EXAMPLE 34B.

Example 29BCis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 29A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.36 (s, 1H), 8.53-8.63 (m, 2H),8.04 (d, 1H), 7.79 (dd, 1H), 7.47-7.56 (m, 3H), 7.34 (d, 2H), 7.00-7.12(m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.37 (s, 1H), 3.26(t, 2H), 3.20 (s, 3H), 3.07 (s, 4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95(s, 2H), 1.81 (dd, 2H), 1.64-1.74 (m, 1H), 1.48 (dd, 2H), 1.23-1.42 (m,6H), 0.92 (s, 6H).

Example 304-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 30A (R)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide

The racemic mixture of EXAMPLE 12A was resolved on a SFC chiral ADcolumn to provide the title compound.

Example 30B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 30A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 2H), 8.35 (s, 1H), 8.03 (d, 2H),7.48-7.57 (m, 3H), 7.42 (d, 1H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd,1H), 6.39 (dd, 1H), 6.21 (s, 1H), 4.19-4.30 (m, 2H), 3.85-3.92 (m, 1H),3.73-3.85 (m, 2H), 3.58-3.70 (m, 2H), 3.40-3.52 (m, 2H), 3.10 (s, 4H),2.85 (s, 2H), 2.18-2.39 (m, 3H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39 (t,2H), 0.93 (s, 6H).

Example 314-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 25A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.66 (s, 1H),11.46 (m, 1H), 8.54 (m, 2H), 8.45 (m, 1H), 8.03 (d, 1H), 7.83 (m, 2H),7.50 (m, 3H), 7.34 (m, 3H), 7.12 (m, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H),6.20 (d, 1H), 4.11 (s, 2H), 3.79 (m, 4H), 3.51 (m, 6H), 3.05 (m, 4H),2.17 (m, 3H), 1.17 (s, 6H).

Example 324-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 12A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.67 (s, 1H),8.37 (d, 1H), 8.03 (m, 2H), 7.50 (m, 3H), 7.37 (d, 2H), 7.13 (d, 2H),6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.25 (m, 2H), 4.12 (s, 2H),3.84 (m, 3H), 3.63 (m, 2H), 3.45 (m, 2H), 3.06 (m, 4H), 2.86 (m, 2H),2.24 (m, 6H), 1.20 (m, 6H).

Example 33Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 9C, respectively.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.63 (s, 1H), 8.51 (d, 1H),8.15 (d, 1H), 8.01 (d, 1H), 7.76 (dd, 1H), 7.48 (m, 3H), 7.38 (d, 2H),7.13 (d, 2H), 7.06 (d, 1H), 6.66 (dd, 1H), 6.36 (dd, 1H), 6.21 (d, 1H),4.11 (s, 2H), 3.63 (m, 5H), 3.05 (m, 4H), 2.83 (s, 2H), 2.64 (m, 4H),2.17 (m, 6H), 2.05 (m, 2H), 1.91 (s, 2H), 1.43 (m, 6H), 1.17 (m, 6H).

Example 34Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 34A (4-methoxycyclohexyl)methanamine

(4-Methoxyphenyl)methanamine (1 g, 1.29 mmol) in ethanol (10 ml) wastreated with 5% Rh—Al₂O₃ (99.8 mg, 0.048 mmol) under H₂ atmosphere (500psi) at 50° C. for 16 hours. Additional 5% Rh—Al₂O₃ (0.4 g) was added.The resulting mixture was stirred under H₂ atmosphere (500 psi) at 60°C. for 2 hours. The insoluble material was filtered off and the filtratewas concentrated to provide a mixture of cis and trans product as anoil, which was used in the next step without further purification.

Example 34BTrans-4-((4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and EXAMPLE 34A (1 g) intetrahydrofuran (20 mL) was treated with N,N-diisopropylethylamine(0.871 mL) overnight. The reaction mixture was concentrated and theresidue was purified by reverse phase chromatography, and was elutedwith 40-55% acetonitrile in 0.1% trifluoroacetic acid in water over 25minutes.

Example 34CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 34B in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.37 (s, 1H), 8.52-8.62 (m, 2H),8.04 (d, 1H), 7.79 (dd, 1H), 7.47-7.55 (m, 3H), 7.34 (d, 2H), 7.02-7.09(m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.21-3.27 (m, 5H),3.02-3.12 (m, 5H), 2.75 (s, 2H), 2.20 (s, 4H), 2.14 (s, 2H), 1.93-2.04(m, 4H), 1.79 (d, 2H), 1.55-1.65 (m, 1H), 1.38 (t, 2H), 0.97-1.12 (m,4H), 0.92 (s, 6H).

Example 354-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 36C,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.65 (s, 1H),8.78 (s, 1H), 8.58 (s, 1H), 8.00 (d, 1H), 7.51 (m, 3H), 7.38 (d, 2H),7.14 (d, 2H), 6.68 (dd, 1H), 6.37 (dd, 1H), 6.23 (d, 1H), 4.31 (d, 2H),4.13 (s, 2H), 3.88 (dd, 2H), 3.11 (m, 5H), 2.16 (m, 6H), 1.65 (m, 2H),1.35 (m, 2H), 1.19 (s, 6H).

Example 364-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 36A

5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in methanol (20 mL)was cooled to 0° C. To this solution was added 7N NH₃ in methanol (80mL). The reaction mixture was stirred overnight. The solvent was removedat low temperature, and the residue was partitioned between ethylacetate and water. The aqueous layer was extracted with ethyl acetatethree times. The combined organic layers were washed with brine, dried(MgSO₄), filtered, and concentrated. The solid was purified by flashcolumn chromatography on silica gel using 20-100% ethyl acetate inhexanes to give the title compound.

Example 36B

The title compound was prepared by substituting EXAMPLE 36A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 36C

A mixture of EXAMPLE 36B (0.702 g), dicyanozinc (0.129 g), andtetrakis(triphenylphosphine)palladium(O) (0.231 g) inN,N-dimethylformamide (2 mL) was degassed via vacuum/nitrogen cyclethree times. The reaction mixture was heated at 120° C. for 3 hours.After cooling, it was poured into water and extracted with ethyl acetatethree times. The combined organic layers were washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified withflash column chromatography on silica gel eluting with 20%-60% ethylacetate in hexanes to give the title compound.

Example 36D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 36C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.56 (s,1H), 8.66 (s, 1H), 8.44 (s, 1H), 7.94 (d, 1H), 7.55 (d, 1H), 7.44 (t,1H), 7.34-7.35 (m, 3H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.32 (s, 1H), 6.24(s, 1H), 4.26 (d, 2H), 3.86 (dd, 2H), 3.10 (s, 4H), 2.75 (s, 2H),2.31-2.35 (m, 2H), 2.01-2.05 (m, 1H), 2.15 (s, 2H), 1.96 (s, 2H),1.63-1.66 (m, 2H), 1.33-1.40 (m, 4H), 0.92 (s, 6H).

Example 374-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 37A 1,6-dioxaspiro[2.5]octane-2-carbonitrile

A mixture of tetrahydropyran-4-one (10 mL) and chloroacetonitrile (6.4mL) in tert-butanol (10 mL) was stirred for 10 minutes. To this solutionwas added a solution of potassium tert-butoxide (12.11 g) in 200 mL oftert-butanol at room temperature over 40 minutes. The reaction mixturewas stirred for 16 hours, diluted with water and quenched slowly with 1N HCl. The solvent was partially removed by rotary evaporation. It wasthen extracted with ether (5×200 mL). The combined extracts was washedwith brine, dried over MgSO₄, filtered, and the filtrate wasconcentrated and purified by flash chromatography on silica with 3:7 to1:1 ethyl acetate:hexanes to provide the title compound.

Example 37B 2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile

EXAMPLE 37A (11.5 g) in dichloromethane (40 mL) in a polypropylenebottle was treated with 70% hydrogen fluoride-pyridine (10.4 mL)dropwise at 0° C. The solution was allowed to warm to room temperatureover 3 hours, and stirred for an additional 1.5 hours. The reactionmixture was diluted with ethyl acetate (200 mL) and poured intosaturated aqueous NaHCO₃. Additional solid NaHCO₃ was used carefullyuntil bubbling ceased. The organic layer was isolated, and the aqueouslayer was extracted with additional ethyl acetate three times (150 mLeach). The combined organic layers were washed with 5% HCl (50 mL each,twice), brine, dried over MgSO₄, filtered and concentrated to give thedesired product which was used directly in the next step.

Example 37C (4-fluorotetrahydro-2H-pyran-4-yl)methanol

EXAMPLE 37B (11.7 g, 74 mmol) in 2-propanol (150 mL) and water (37.5 mL)was cooled to 0° C. To this solution was added NaBH₄ (4.20 g, 111 mmol).The solution was stirred and allowed to warm to room temperature over 3hours. It was quenched with acetone, and stirred for another 1 hour. Theclear liquid was separated from solid by decanting. Additional ethylacetate (2×100 mL) was used to wash the solid, and the mixture wasdecanted. The combined organic solutions were concentrated. The residuewas purified by flash chromatography, eluting with 1:1 ethylacetate:hexanes to provide the title compound.

Example 37D4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 37C for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 37E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 37D in place of EXAMPLE 11B. ¹H NMR (dimethylsulfoxide-d₆).11.64 (s, 2H), 8.33 (s, 1H), 8.00-8.01 (m, 2H), 7.39-7.57 (m, 4H), 7.33(d, J=8.24 Hz, 2H), 7.03 (d, J=8.54 Hz, 2H), 6.65 (dd, J=9, 1.98 Hz,1H), 6.37-6.38 (m, 1H), 6.19 (d, J=1.53 Hz, 1H), 4.35 (d, J=20.75 Hz,2H), 3.74-3.78 (m, 2H), 3.55-3.60 (m, 2H), 3.07 (br, 4H), 2.80 (br, 2H),2.25 (br, 4H), 2.13 (br, 2H), 1.81-1.94 (m, 6H), 1.38 (t, J=6.26 Hz,2H), 0.91 (s, 6H).

Example 38N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 38A3-cyano-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

The title compound was prepared by substituting3-cyano-4-fluorobenzenesulfonamide for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 38B 5-sulfamoyl-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide

To a solution of EXAMPLE 38A (0.455 g) in ethanol (3 mL) andtetrahydrofuran (1 mL) was added hydrogen peroxide (30% in water, 2 mL)followed by 1 N aqueous NaOH (1.024 ml) and heated to 35° C. for 3hours. The reaction was poured into dichloromethane (50 mL) and 1Naqueous HCl (25 mL). The aqueous layer was extracted withdichloromethane (3×50 mL). The precipitate contained in the combinedorganic layers was collected by filtration to give the title compound.

Example 38CN-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 38B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.79-11.70 (m, 1H), 11.66-11.54 (m, 1H),9.29-9.08 (m, 1H), 8.27 (d, 1H), 8.08 (d, 1H), 7.97-7.90 (m, 1H),7.76-7.72 (m, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.50 (d, 1H), 7.39 (d,1H), 7.23 (d, 1H), 7.08 (d, 1H), 6.74-6.67 (m, 1H), 6.44 (s, 1H), 6.22(s, 1H), 4.03 (d, 6H), 3.74-3.52 (m, 4H), 3.33 (s, 4H), 3.11-2.90 (m,2H), 2.01 (s, 4H), 1.79-1.58 (m, 2H), 1.24 (s, 5H), 0.94 (s, 6H).

Example 39Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 39A Cis-tert-butyl-4-morpholinocyclohexylcarbamate

To a solution of morpholine (4.08 g) and tert-butyl4-oxocyclohexylcarbamate (10 g) stirred for 24 hours at room temperaturein titanium (IV) isopropoxide (27.5 mL), methanol (10 mL) was addedfollowed by careful addition of sodium borohydride (3.55 g). Thereaction mixture was quenched with water/NaOH solution, extracted withether, dried over magnesium sulfate, filtered, and concentrated. Theproduct was separated from the trans isomer and purified by flashchromatography (silica gel, 50%-100% acetone in hexanes) to provide thetitle compound.

Example 39B cis-4-morpholinocyclohexanamine bis(2,2,2-trifluoroacetate)

To a solution of EXAMPLE 39A (2.43 g) in dichloromethane (15 ml) wasadded trifluoroacetic acid (5 ml) and the reaction mixture was stirredfor 16 hours at room temperature. The reaction mixture was concentratedand the crude product was used without purification.

Example 39C4-(cis-4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide

A solution of EXAMPLE 39B (0.40 g), 4-fluoro-3-nitrobenzenesulfonamide(0.478 g) and triethylamine (2 mL) in tetrahydrofuran (10 mL) wasstirred for 3 days at room temperature. The reaction mixture wasconcentrated and purified by flash chromatography (silica gel, 0-30%methanol/dichloromethane) providing the product.

Example 39DCis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 39C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.07 (s, 1H), 9.30(d, 1H), 8.64 (d, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H), 7.67(t, 2H), 7.44 (d, 2H), 7.06 (d, 2H), 6.91 (d, 1H), 6.74 (dd, 1H),6.48-6.55 (m, 2H), 3.65-3.73 (m, 5H), 3.02-3.09 (m, 4H), 2.76 (s, 2H),2.41-2.48 (m, 4H), 2.25 (t, 2H), 2.09-2.16 (m, 5H), 1.97 (s, 2H),1.77-1.86 (m, 2H), 1.55-1.63 (m, 6H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 404-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 40A 5,6-dichloropyridine-3-sulfonamide

The title compound was prepared by substituting5,6-dichloropyridine-3-sulfonyl chloride for5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 36A.

Example 40B5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 40C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.52 (s, 1H), 8.39 (d, 1H), 8.03 (d, 1H), 7.54 (d, 1H), 7.52 (d,1H), 7.50 (dd, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (m,1H), 6.21 (d, 1H), 4.25 (d, 2H), 3.87 (dd, 2H), 3.30 (m, 2H), 3.10 (v brs, 4H), 2.90 (v br s, 2H), 2.35 (v br s, 4H), 2.17 (br m, 2H), 2.05 (m,1H), 1.96 (s, 2H), 1.64 (d, 2H), 1.40 (t, 2H), 1.35 (ddd, 2H), 0.93 (s,6H).

Example 414-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 15H for EXAMPLE3J and EXAMPLE 40B for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 8.55 (d, 1H), 8.41 (d, 1H), 8.04(d, 1H), 7.54 (m, 2H), 7.50 (dd, 1H), 7.38 (d, 2H), 7.14 (d, 2H), 6.68(dd, 1H), 6.40 (m, 1H), 6.20 (d, 1H), 4.25 (d, 2H), 4.12 (s, 2H), 3.87(dd, 2H), 3.30 (m, 2H), 3.10 (v br s, 4H), 2.90 (v br s, 2H), 2.27 (v brs, 4H), 2.17 (br m, 2H), 2.05 (m, 1H), 1.96 (s, 2H), 1.64 (d, 2H), 1.35(ddd, 2H), 0.97 (s, 6H).

Example 424-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamideExample 42A4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethyl)benzenesulfonamide

A mixture of 4-fluoro-3-(trifluoromethyl)benzenesulfonamide (1.056 g),(tetrahydro-2H-pyran-4-yl)methanamine (0.5 g) andN,N-diisopropylethylamine (1.68 g) in anhydrous dimethylsulfoxide (15mL) solution was heated at 90° C. overnight. The reaction mixture wascooled to room temperature and diluted with ethyl acetate. The organicphase was washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated to afford the title compound.

Example 42B4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 42A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.73 (s, 1H),11.25 (s, 1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.77 (m, 1H), 7.61 (d, 1H),7.51 (m, 2H), 7.37 (d, 2H), 7.13 (d, 2H), 6.88 (d, 1H), 6.67 (dd, 1H),6.53 (m, 1H), 6.43 (m, 1H), 6.15 (d, 1H), 4.11 (s, 2H), 3.82 (dd, 2H),3.19 (m, 5H), 3.05 (m, 4H), 2.82 (s, 2H), 2.20 (m, 7H), 1.85 (m, 1H),1.56 (m, 2H), 1.18 (s, 6H).

Example 434-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 17A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.69 (s, 1H),11.48 (m, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.92 (dd, 1H), 7.52 (m, 3H),7.37 (d, 2H), 7.27 (m, 1H), 7.11 (m, 3H), 6.68 (dd, 1H), 6.41 (dd, 1H),6.18 (d, 1H), 4.11 (s, 2H), 3.84 (dd, 2H), 3.25 (m, 4H), 3.07 (m, 4H),2.84 (m, 2H), 2.23 (m, 5H), 1.84 (m, 1H), 1.55 (m, 2H), 1.25 (m, 3H),1.18 (s, 6H).

Example 44Trans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 44ATrans-4-(4-morpholinocyclohexylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

The title compound was prepared as described in EXAMPLE 16A by replacing2-methoxyethanamine with EXAMPLE 9B.

Example 44BTrans-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 44A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.62 (s, 1H),8.08 (s, 1H), 8.00 (d, 1H), 7.85 (d, 1H), 7.47 (m, 3H), 7.38 (d, 2H),7.14 (d, 2H), 6.98 (d, 1H), 6.65 (dd, 1H), 6.55 (m, 1H), 6.37 (m, 1H),6.21 (d, 1H), 4.12 (s, 2H), 3.54 (m, 6H), 3.04 (m, 4H), 2.83 (s, 2H),2.57 (m, 3H), 2.24 (m, 6H), 1.91 (m, 5H), 1.34 (m, 4H), 1.20 (s, 6H).

Example 454-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 45A4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

The title compound was prepared as described in EXAMPLE 16A by replacing2-methoxyethanamine with 1-methyl-4-aminopiperidine.

Example 45B4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 45A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.59 (s, 1H),8.10 (s, 1H), 7.98 (d, 1H), 7.90 (dd, 1H), 7.49 (m, 3H), 7.39 (m, 3H),7.14 (d, 2H), 7.02 (d, 1H), 6.65 (dd, 2H), 6.36 (dd, 1H), 6.22 (d, 1H),4.12 (s, 2H), 3.75 (m, 1H), 3.16 (m, 4H), 2.98 (m, 5H), 2.88 (m, 5H),2.67 (s, 2H), 2.22 (m, 6H), 1.68 (m, 1H), 1.18 (s, 6H).

Example 465-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethoxy)nicotinamide5-sulfamoyl-2-((tetrahydro-2H-pyran-4-yl)methoxy)nicotinamide

To EXAMPLE 36C (0.025 g) in ethanol (1 mL) and tetrahydrofuran (1 mL)was added hydrogen peroxide (30% in water, 0.5 mL) followed by 1Maqueous sodium hydroxide (0.056 ml) then another 1 mL oftetrahydrofuran. The reaction was heated to 45° C. for 2 hours, cooled,quenched with 1N aqueous HCl (5 mL), and the product extracted intodichloromethane (10 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated to give the title compound.

Example 46B5-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethoxy)nicotinamide

The title compound was prepared by substituting EXAMPLE 46A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz, CDCl₃)δ 10.31-10.09 (m, 1H), 9.09 (s, 2H), 8.93-8.81 (m, 1H), 8.28-8.18 (m,1H), 8.03-7.87 (m, 1H), 7.77-7.68 (m, 1H), 7.59-7.51 (m, 1H), 7.48-7.41(m, 1H), 6.91 (d, 2H), 6.59-6.48 (m, 2H), 5.97 (s, 2H), 4.50 (d, 2H),4.08-3.98 (m, 2H), 3.45 (s, 4H), 3.13-2.99 (m, 4H), 2.82-2.68 (m, 2H),2.19 (s, 4H), 1.86 (s, 5H), 1.61-1.35 (m, 4H), 0.94 (s, 6H).

Example 47N-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 47A5-bromo-6-((1-methylpiperidin-4-yl)methoxy)pyridine-3-sulfonamide

To (1-methylpiperidin-4-yl)methanol (0.109 g) in tetrahydrofuran (2 mL)was added sodium hydride (0.136 g). After 30 minutes, EXAMPLE 36A (0.230g) was added as a solution in tetrahydrofuran (1 mL) and the reactionwas heated to 50° C. After 4 hours, the reaction was cooled, poured intowater (10 mL) and dichloromethane (50 mL), and the pH was adjusted topH-8. The aqueous layer was extracted with dichloromethane (3×50 mL),and the organic layers were combined, washed with brine (30 mL), driedover magnesium sulfate, filtered, and concentrated to give the titlecompound.

Example 47BN-({5-bromo-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 47A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.51 (s, 1H), 8.35 (d, 1H), 8.17 (d, 1H), 7.93(d, 1H), 7.60 (d, 1H), 7.44-7.40 (m, 1H), 7.33 (dd, 3H), 7.05 (d, 2H),6.61 (d, 1H), 6.31 (dd, 1H), 6.24 (s, 1H), 4.25 (d, 2H), 3.40 (s, 4H),3.01 (s, 4H), 2.73 (d, J=8.2, 5H), 2.20 (s, 6H), 1.93 (d, 4H), 1.54 (s,1H), 1.39 (s, 2H), 1.24 (s, 2H), 0.93 (s, 6H).

Example 484-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 48A4-((1-methylpiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting(1-methylpiperidin-4-yl)methanol for (tetrahydro-2H-pyran-4-yl)methanolin EXAMPLE 24A.

Example 48B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 48A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.54 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H),7.87-7.77 (m, 1H), 7.58 (d, 1H), 7.43 (s, 1H), 7.40-7.00 (m, 7H),6.70-6.56 (m, 1H), 6.31 (s, 1H), 6.24 (s, 1H), 4.05 (s, 2H), 3.46-3.33(m, 2H), 3.02 (s, 6H), 2.72 (d, 5H), 2.21 (s, 6H), 1.96 (s, 5H),1.70-1.48 (m, 2H), 1.39 (s, 2H), 0.93 (s, 6H).

Example 494-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 49A 6-((1, 4-dioxan-2-yl)methoxy)-5-bromopyridine-3-sulfonamide

The title compound was prepared by substituting (1,4-dioxan-2-yl)methanol for (tetrahydro-2H-pyran-4-yl)methanol andEXAMPLE 36A for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 49B 6-((1,4-dioxan-2-yl)methoxy)-5-cyanopyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 49A for EXAMPLE36B in EXAMPLE 36C.

Example 49C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 49B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.50 (s,1H), 8.60 (s, 1H), 8.40 (s, 1H), 7.91 (d, 1H), 7.58 (d, 1H), 7.42 (t,1H), 7.35 (d, 2H), 7.28 (s, 1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.29 (m,2H), 4.40 (d, 2H), 3.90 (m, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.46 (m,4H), 3.07 (s, 4H), 2.85 (m, 2H), 2.34 (m, 4H), 2.16 (m, 2H), 1.40 (t,2H), 0.93 (s, 6H).

Example 50N-{[5-bromo-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 49A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.60 (s,1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.99 (d, 1H), 7.56 (d, 1H), 7.46 (m,2H), 7.35 (d, 2H), 7.05 (d, 2H), 6.65 (dd, 1H), 6.36 (dd, 1H), 6.22 (d,1H), 4.34 (m, 2H), 3.88 (m, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.46 (m,2H), 3.06 (s, 4H), 2.81 (s, 2H), 2.26 (m, 4H), 2.15 (s, 2H), 1.96 (s,2H), 1.38 (m, 2H), 0.93 (s, 6H).

Example 514-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 51A

The title compound was prepared as described in EXAMPLE 12A by replacing(1,4-dioxan-2-yl)methanol with(2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol.

Example 51B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 51A in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 2H), 8.35 (s, 2H), 8.03 (d, 4H),7.47-7.58 (m, 6H), 7.31-7.42 (m, 6H), 7.04 (d, 4H), 6.68 (dd, 2H), 6.40(s, 2H), 6.20 (d, 2H), 3.96-4.09 (m, 2H), 3.54-3.68 (m, 2H), 3.09 (s,4H), 2.83 (s, 2H), 2.09-2.37 (m, 7H), 1.96 (s, 2H), 1.55-1.69 (m, 2H),1.39 (t, 2H), 1.19 (m, 8H), 0.92 (s, 6H).

Example 52N-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 52A 3-cyano-4-fluorobenzenesulfonamide

3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.1 g) in 1,4-dioxane (10mL) at 0° C. was treated dropwise with a 7 M ammonia solution inmethanol (3.57 mL) and stirred for 30 minutes. A small amount of solidwas removed by filtration and discarded. The filtrate was concentrated,diluted with ethyl acetate, washed with water and brine, dried (MgSO₄),filtered, concentrated and triturated with diethyl ether to give theproduct.

Example 52B3-cyano-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 52A for4-chloro-3-nitrobenzenesulfonamide and(tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-aminedihydrochloride in EXAMPLE 6A.

Example 52C3-chloro-5-cyano-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

EXAMPLE 52B (0.148 g) in acetonitrile (5 mL) was treated withN-chlorosuccinimide (0.080 g), heated at 60° C. for 3 hours and filteredto remove a small amount of solid. The filtrate was concentrated andchromatographed on silica gel with 3-15% ethyl acetate indichloromethane as eluent. The obtained solid was slurried in water,filtered, rinsed with additional water and dried under vacuum to givethe product.

Example 52DN-({3-chloro-5-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 52C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.70 (s,1H), 11.41 (br s, 1H), 8.07 (d, 1H), 7.89 (s, 2H), 7.61 (m, 1H), 7.53(m, 2H), 7.35 (d, 2H), 7.18 (m, 1H), 7.05 (d, 2H), 6.69 (m, 1H), 6.42(dd, 1H), 6.18 (dd, 1H), 3.83 (m, 2H), 3.55 (t, 2H), 3.23 (m, 3H), 3.06(m, 4H), 2.15 (m, 4H), 1.92 (m, 4H), 1.60 (m, 2H), 1.40 (m, 2H), 1.19(m, 4H), 0.93 (s, 6H).

Example 53N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 53AN-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE 1G.

Example 53BN-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A 5 mL round-bottomed flask was charged with EXAMPLE 53A (120 mg),1-acetylpiperidin-4-amine (28 mg), and triethylamine (0.064 mL) indioxane (2 ml). The reaction mixture was heated to 90° C. for 24 hours.The reaction mixture was cooled to room temperature, and added to asilica gel column and purified by eluting with 0-5% methanol indichloromethane. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.66 (br s,1H), 8.65 (d, 1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.83 (dd, 1H), 7.54-7.46(m, 3H), 7.35 (d, 2H), 7.19 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39(m, 1H), 6.20 (d, 1H), 4.28 (d, 1H), 3.97-3.75 (m, 2H), 3.07 (br s, 4H),2.87-2.70 (m, 4H), 2.29-2.10 (m, 6H), 2.02 (s, 3H), 2.00-1.89 (m, 4H),1.66-1.54 (m, 2H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 54N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 54A2-chloro-5-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting2-chloro-4,5-difluorobenzenesulfonamide for4-chloro-3-nitrobenzenesulfonamide and(tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-aminedihydrochloride in EXAMPLE 6A.

Example 54N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 54A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.76 (s,1H), 11.31 (s, 1H), 8.08 (d, 1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.55 (m,2H), 7.34 (d, 2H), 7.04 (d, 2H), 6.90 (s, 1H), 6.84 (d, 1H), 6.69 (dd,1H), 6.45 (dd, 1H), 6.13 (d, 1H), 3.82 (dd, 2H), 3.24 (t, 2H), 3.05 (m,6H), 2.73 (s, 2H), 2.14 (m, 6H), 1.95 (s, 2H), 1.81 (m, 1H), 1.61 (m,2H), 1.38 (t, 2H), 1.17 (m, 2H), 0.92 (s, 6H).

Example 554-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.66 (br s, 1H), 8.75 (t, 1H), 8.54 (d, 1H),8.03 (d, 1H), 7.79 (dd, 1H), 7.54-7.48 (m, 3H), 7.35 (d, 2H), 7.08-7.02(m, 3H), 6.67 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 3.61 (t, 4H), 3.43(q, 2H), 3.29 (m, 2H), 3.06 (br s, 4H), 2.73 (br s, 2H), 2.47 (br s,4H), 2.18 (m, 6H), 1.95 (br s, 2H), 1.80 (m, 2H), 1.38 (t, 2H), 0.92 (s,6H).

Example 564-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 56A5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 37C fortetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 36A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 56B

The title compound was prepared by substituting EXAMPLE 56A for EXAMPLE36B in EXAMPLE 36C.

Example 56C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 56B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.58 (s,1H), 8.70 (s, 1H), 8.51 (s, 1H), 7.96 (d, 1H), 7.57 (d, 1H), 7.45 (t,1H), 7.35-7.37 (m, 3H), 7.06 (d, 2H), 6.67 (dd, 1H), 6.33 (d, 1H), 6.26(s, 1H), 4.56 (d, 2H), 3.76-3.80 (s, 2H), 3.56-3.62 (m, 2H), 3.01-3.10(m, 4H), 2.14-2.18 (m, 2H), 1.96 (s, 2H), 1.80-1.87 (m, 4H), 1.41 (t,2H), 0.93 (s, 6H).

Example 574-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 57A 5-bromo-6-(2-morpholinoethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting 2-morpholinoethanol fortetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 36A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 57B 5-cyano-6-(2-morpholinoethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 57A for EXAMPLE36A in EXAMPLE 36B.

Example 57C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 57B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.56 (s,1H), 8.64 (s, 1H), 8.41 (s, 1H), 7.92 (d, 1H), 7.58 (d, 1H), 7.44 (t,1H), 7.36 (d, 2H), 7.31 (s, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.31 (d,1H), 6.27 (d, 1H), 4.59 (t, 2H), 3.59 (s, 4H), 3.08 (s, 4H), 2.89 (s,2H), 2.65 (s, 4H), 2.16-2.18 (m, 2H), 1.97 (s, 2H), 1.41 (t, 2H), 0.93(s, 6H).

Example 58N-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 58A 3-chloro-4-(2-(2-methoxyethoxy)ethylthio)benzenesulfonamide

In a 25 mL microwave tube was added sodium hydride (0.6 g) intetrahydrofuran (10 mL) to give a suspension.2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After stirringfor 30 minutes, 3-chloro-4-fluorobenzenesulfonamide (1.54 g) dissolvedin 10 mL tetrahydrofuran was added slowly. The mixture was heated at110° C. for 30 minutes in a Biotage Initiator microwave reactor. Waterwas added, the product was extracted with ether (20 mL×3), dried overNa₂SO₄, filtered, and the solvent was removed under reduced pressure.The crude product was purified by flash chromatography on silica elutingwith 0-25% ethyl acetate in hexane.

Example 58B3-chloro-4-(2-(2-methoxyethoxy)ethylsulfonyl)benzenesulfonamide

EXAMPLE 58A (0.15 g) was suspended in acetic acid (3 mL). Peracetic acid(0.4 mL) was added slowly. The mixture was stirred at room temperatureovernight, then poured into Na₂S₂O₃ solution, and the productprecipitated. After filtration and washing with water, the product wasdried under vacuum.

Example 58CN-[(3-chloro-4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.52 (s,1H), 7.92 (d, 1H), 7.84 (m, 2H), 7.68 (m, 1H), 7.62 (d, 1H), 7.42 (t,1H), 7.35 (d, 2H), 7.29 (m, 1H), 7.05 (d, 2H), 6.62 (dd, 1H), 6.32 (m,1H), 6.26 (d, 1H), 3.74 (t, 2H), 3.68 (t, 2H), 3.24 (m, 2H), 3.06 (m,5H), 3.01 (m, 4H), 2.74 (s, 2H), 2.19 (m, 6H), 1.96 (s, 2H), 1.39 (t,2H), 0.93 (s, 6H).

Example 594-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 59A 4-(2-(2-methoxyethoxy)ethylthio)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting4-fluoro-3-nitrobenzenesulfonamide for3-chloro-4-fluorobenzenesulfonamide in EXAMPLE 58A.

Example 59B4-(2-(2-methoxyethoxy)ethylsulfonyl)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 59A for EXAMPLE58A in EXAMPLE 58B.

Example 59C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 59B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.51 (s,1H), 8.17 (m, 1H), 7.94 (m, 3H), 7.64 (d, 1H), 7.42 (m, 1H), 7.35 (d,2H), 7.28 (d, 1H), 7.05 (d, 2H), 6.62 (m, 1H), 6.28 (m, 2H), 3.83 (m,4H), 3.16 (m, 2H), 3.08 (s, 3H), 3.01 (m, 4H), 2.73 (s, 2H), 2.18 (m,6H), 1.96 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H)

Example 60Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 60A Trans-4-(4-aminocyclohexyloxy)-3-nitrobenzenesulfonamide

To a solution of tert-butyl 4-hydroxycyclohexylcarbamate (0.250 g) intetrahydrofuran (5 mL) was added sodium hydride (0.186 g). Afterstirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.256 g)was added as a solution in tetrahydrofuran (1 mL). The reaction washeated to 60° C. for 1.5 hours, cooled, and poured into a mixture ofdichloromethane (100 mL) and water (25 ml). The aqueous layer wasadjusted to pH-4 with 1N aqueous HCl and the organic layer wasseparated, washed with brine (50 ml), dried over magnesium sulfate,filtered, and concentrated. The residue was loaded onto silica gel(GRACERESOLV 40 g) and eluted using a gradient of 0.5% to 7.5%methanol/dichloromethane over 30 minutes. This solid was treated withHCl (4.0M in dioxane, 5 ml) at room temperature for 1 hour andconcentrated to give the title compound.

Example 60B4-(trans-4-morpholinocyclohexyloxy)-3-nitrobenzenesulfonamide

To EXAMPLE 60A (0.220 g) and 1-bromo-2-(2-bromoethoxy)ethane (0.177 g)in N,N-dimethylformamide (3 mL) was added triethylamine (0.338 ml) andthe reaction heated to 70° C. for 5 hours. The reaction was cooled andthe resulting precipitate was removed by filtration. The reaction wasconcentrated and loaded onto silica gel and was eluted using a gradientof 0.5% to 7.5% methanol/dichloromethane to give the title compound.

Example 60CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 60B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.62 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H),7.96-7.88 (m, 1H), 7.54 (d, 1H), 7.48 (s, 2H), 7.34 (d, 3H), 7.04 (d,2H), 6.72-6.58 (m, 1H), 6.37 (s, 1H), 6.21 (s, 1H), 4.69-4.47 (m, 1H),3.66 (s, 4H), 3.05 (s, 4H), 2.76 (s, 6H), 2.22 (s, 9H), 1.96 (s, 4H),1.39 (s, 6H), 0.92 (s, 6H).

Example 61N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 61A5-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)pyridine-3-sulfonamide

A mixture of EXAMPLE 36A (1.0 g), EXAMPLE 3L (0.95 g) and triethylamine(3.08 mL) in anhydrous dioxane (20 mL) was heated at 110° C. overnight.The organic solvent was removed under vacuum. The residue was purifiedwith flash column chromatography on silica gel eluting with 2%-8%methanol/dichloromethane to give the title compound.

Example 61BN-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 61A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.59 (s,1H), 8.35 (s, 1H), 8.00 (s, 2H), 7.55 (d, 1H), 7.46 (m, 2H), 7.34 (d,2H), 7.04 (d, 2H), 6.63 (dd, 1H), 6.49 (m, 1H), 6.36 (s, 1H), 6.20 (s,1H), 4.05 (m, 1H), 3.94 (d, 2H), 3.28 (m, 6H), 3.01 (s, 4H), 2.72 (s,2H), 2.16 (m, 6H), 1.93 (m, 4H), 1.80 (m, 4H), 1.57 (m, 2H), 1.38 (t,2H), 1.17 (t, 2H), 0.90 (s, 6H).

Example 624-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 62A 4-(2-cyanoethylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 3-aminopropanenitrilefor EXAMPLE 39B in EXAMPLE 39C.

Example 62B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 62A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (501 MHz, pyridine-d₅) δ 13.04 (s, 1H), 9.24(d, 1H), 9.04 (t, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.13 (d, 1H),7.64-7.68 (m, 2H), 7.44 (ddd, 2H), 7.07 (ddd, 2H), 7.02 (d, 1H), 6.76(dd, 1H), 6.55 (d, 1H), 6.48 (dd, 1H), 3.83 (q, 2H), 3.07 (d, 4H), 2.98(t, 2H), 2.77 (s, 2H), 2.26 (s, 2H), 2.11-2.17 (m, 4H), 1.97 (s, 2H),1.39 (t, 2H), 0.93 (s, 6H).

Example 63Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 15H for EXAMPLE3J and EXAMPLE 39C for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (501 MHz,pyridine-d₅) δ 13.09 (s, 1H), 9.30 (d, 1H), 8.64 (d, 1H), 8.43 (d, 1H),8.38 (dd, 1H), 8.10 (d, 1H), 7.68 (dt, 2H), 7.46 (ddd, 2H), 7.12 (ddd,2H), 6.91 (d, 1H), 6.72 (dd, 1H), 6.51 (dd, 1H), 6.49 (d, 1H), 5.69 (s,2H), 4.40 (s, 2H), 3.69-3.73 (m, 4H), 3.68 (s, 1H), 2.95-3.02 (m, 4H),2.84 (s, 2H), 2.40-2.46 (m, 4H), 2.21 (s, 2H), 2.08-2.15 (m, 5H),1.76-1.84 (m, 2H), 1.55-1.63 (m, 6H), 1.29 (s, 6H).

Example 64Trans-N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 64A tert-butyl(trans)-4-(bis(cyclopropylmethyl)amino)cyclohexylcarbamate

The title compound was prepared by substituting cyclopropanecarbaldehydefor 4′-chlorobiphenyl-2-carboxaldehyde and tert-butyl(trans)-4-aminocyclohexylcarbamate for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 64B (trans)-N¹,N¹-bis(cyclopropylmethyl)cyclohexane-1,4-diaminedihydrochloride

To a solution of EXAMPLE 64A (1.4 g) in dichloromethane (10 ml) wasadded hydrogen chloride (10 ml, 4M in dioxane) and the reaction wasstirred for 16 hours at room temperature. The reaction mixture wasdiluted with ether and pure product was filtered off.

Example 64CTrans-4-(4-(bis(cyclopropylmethyl)amino)cyclohexylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 64B for EXAMPLE39B in EXAMPLE 39C.

Example 64DTrans-N-{[4-({4-[bis(cyclopropylmethyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 64C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H), 9.30(d, 1H), 8.44 (d, 1H), 8.41 (dd, 1H), 8.37 (d, 1H), 8.12 (d, 1H), 7.67(d, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 7.00 (d, 1H), 6.75 (dd, 1H), 6.53(d, 1H), 6.49 (dd, 1H), 3.36-3.43 (m, 1H), 3.02-3.09 (m, 4H), 2.87-2.94(m, 1H), 2.77 (s, 2H), 2.47 (d, 4H), 2.25 (t, 2H), 2.11-2.16 (m, 4H),2.08 (d, 2H), 1.97 (s, 2H), 1.84 (d, 2H), 1.39 (t, 2H), 1.26-1.35 (m,4H), 0.90-0.98 (m, 8H), 0.50-0.56 (m, 4H), 0.18-0.23 (m, 4H).

Example 654-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 65A4-((1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 4-aminomethyl-1-methylpiperidine for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 65B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 65A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, dichloromethane-d₂) δ 9.57 (bs,1H), 8.78 (d, 1H), 8.41 (d, 1H), 8.14 (d, 1H), 7.90 (m, 2H), 7.64 (d,1H), 7.45 (d, 1H), 7.23 (d, 2H), 6.95 (d, 2H), 6.76 (d, 1H), 6.59 (dd,1H), 6.51 (d, 1H), 6.09 (d, 1H), 3.21 (m, 2H), 3.08 (m, 4H), 3.02 (m,2H), 2.74 (s, 2H), 2.33 (s, 3H), 2.21-2.17 (m, 6H), 2.16-2.02 (m, 3H),1.97 (br. s, 2H), 1.78 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).

Example 664-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 66A tert-butyl3-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting tert-butyl3-(aminomethyl)morpholine-4-carboxylate for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 66B tert-butyl3-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 66A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1F, with the exception thatthe product was purified on a silica gel column eluted with 4% methanolin dichloromethane.

Example 66C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-3-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A solution of EXAMPLE 66B in 50% trifluoroacetic acid anddichloromethane mixture was stirred at ambient temperature for 2 hours.The solvents were evaporated and the residue was purified on a reversephase HPLC using a gradient of 20-80% acetonitrile in water containing10 mM ammonium acetate. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.61(s, 1H), 8.52 (bs, 1H), 8.49 (d, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.54(d, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.34 (d, 2H), 7.04 (m, 3H), 6.65(dd, 1H), 6.34 (s, 1H), 6.21 (d, 1H), 3.89 (d, 1H), 3.76 (d, 1H),3.55-3.46 (m, 2H), 3.40-3.35 (m, 4H), 3.04 (m, 4H), 2.91 (t, 1H), 2.73(s, 2H), 2.20-2.12 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 674-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 15H and EXAMPLE 6A, respectively.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.58 (s, 1H), 9.04 (s, 1H),8.44 (d, 1H), 7.97 (d, 1H), 7.76 (dd, 1H), 7.49 (m, 4H), 7.38 (d, 2H),7.14 (d, 2H), 6.64 (dd, 1H), 6.34 (d, 1H), 6.21 (d, 1H), 4.12 (s, 2H),3.03 (m, 6H), 2.85 (m, 5H), 2.29 (m, 4H), 2.18 (m, 6H), 1.20 (s, 6H).

Example 684-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 68A 4-morpholinobut-2-yn-1-ol

To a solution of morpholine (4.36 g) in toluene (15 mL) was added4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 mL). The solution wasstirred at 85° C. for 3 hours. After cooling, the solid was filteredoff. The filtrate was subjected to vacuum distillation to give the puretitle compound.

Example 68B 4-(4-morpholinobut-2-ynyloxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 68A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 68C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 68B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.68 (s,1H), 8.36 (s, 1H), 8.08 (d, 1H), 8.03 (d, 1H), 7.47-7.53 (m, 4H), 7.35(d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 5.15(s, 2H), 3.52-3.55 (m, 4H), 3.09 (s, 4H), 2.84 (br s, 2H), 2.23-2.40 (m,6H), 2.12-2.18 (m, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 694-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 69A6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide

EXAMPLE 36B (0.176 g), bis(triphenylphosphine)palladium(II) chloride(0.176 g), copper(I) iodide (0.010 g), N,N-dimethylacetamide (2.5 mL)and triethylamine (0.105 mL) were combined, flushed with nitrogen andstirred for 2 minutes. (Triisopropylsilyl)acetylene (0.135 mL) was addedand the reaction mixture was flushed with nitrogen again, heated at 60°C. overnight, diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), filtered, concentrated and chromatographed on silica gelwith 10-30% ethyl acetate in hexanes as the eluent to give the product.

Example 69B5-ethynyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 69A (0.205 g) in tetrahydrofuran (3 mL) at ambient temperaturewas treated with tetrabutyl ammonium fluoride (1 M in tetrahydrofuran,0.906 mL) and stirred at ambient temperature for 4 hours. Additionaltetrabutyl ammonium fluoride (1 M in tetrahydrofuran, 1.8 mL) was addedand the mixture was heated at 40° C. for 45 minutes. Solid tetrabutylammonium fluoride (0.253 g) was added and heating was continued for 30minutes. The reaction mixture was concentrated and then chromatographedon silica gel using 0-2% methanol in dichloromethane as the eluent togive the product.

Example 694-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 69B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.69 (s,1H), 11.41 (s, 1H), 8.58 (d, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.53 (m,3H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.41 (dd, 1H), 6.18 (d,1H), 4.56 (s, 1H), 4.24 (d, 2H), 3.87 (dd, 2H), 3.38 (m, 3H), 3.07 (m,4H), 2.86 (m, 2H), 2.29 (m, 5H), 2.04 (m, 3H), 1.64 (dd, 2H), 1.34 (m,4H), 0.93 (s, 6H).

Example 704-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-oxo-3,4-dihydroquinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 70A 4-amino-3-cyanobenzenesulfonamide

3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.1 g) was dissolved indioxane (4 mL). The solution was cooled to 0° C. and 7 mL of an ammonia(7N in methanol) solution was added. After the addition was complete,the ice bath was removed and the reaction was stirred at roomtemperature for 24 hours. After concentration of the reaction mixture,the crude material was purified by flash chromatography eluting with agradient of 30-100% ethyl acetate/hexanes.

Example 70B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-amino-3-cyanophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 70A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G.

Example 70C2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-amino-3-carbamoylphenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

To a solution of EXAMPLE 70B (90 mg) in ethanol (2 mL) was addedtetrahydrofuran (2 mL), hydrogen peroxide (30%, 1 mL) and 1M sodiumhydroxide solution (0.48 mL), followed by an additional 2 mL oftetrahydrofuran. The reaction was heated to 45° C. for 30 minutes,cooled, and then quenched with 5% HCl solution and extracted twice withdichloromethane. The extracts were combined and concentrated to obtainthe product.

Example 70D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-oxo-3,4-dihydroquinazolin-6-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 70C (80 mg) was combined with trimethyl orthoformate (2.3 mL)and trifluoroacetic acid (0.03 mL) and the resulting solution wasstirred at room temperature for 4 hours. The mixture was purified byflash chromatography, eluting with a gradient of 3-10%methanol/dichloromethane. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.61(s, 1H), 11.71 (s, 1H), 8.65 (d, 1H), 8.24 (s, 1H), 8.17 (dd, 1H), 8.04(m, 1H), 7.73 (d, 1H), 7.57 (d, 1H), 7.51 (m, 2H), 7.39 (d, 2H), 7.07(d, 2H), 6.70 (dd, 1H), 6.40 (m, 1H), 6.24 (br s, 1H), 3.61 (m, 6H),3.03 (m, 2H), 2.75 (m, 2H), 2.17 (m, 2H), 2.01 (m, 2H), 1.44 (m, 2H),0.94 (s, 6H).

Example 71Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 71A 8-chlorospiro[4.5]dec-7-ene-7-carbaldehyde

To a solution of N,N-dimethylformamide (2.81 mL) in dichloromethane (40mL) was added dropwise POCl₃ (2.78 mL) at 0° C. The reaction mixture waswarmed up to room temperature and spiro[4.5]decan-8-one (3.95 g) indichloromethane (5 mL) was added dropwise. The mixture was stirredovernight. The reaction was quenched with cold aqueous sodium acetateand the resulting mixture was extracted with ether and the organic layerwas dried over Na₂SO₄, filtered, and concentrated to provide the titlecompound.

Example 71B 8-(4-chlorophenyl)spiro[4.5]dec-7-ene-7-carbaldehyde

To a suspension of EXAMPLE 71A (3 g) in water (50 mL) was added4-chlorophenylboronic acid (2.83 g), tetrabutylammonium (4.87 g),potassium carbonate (6.26 g) and palladium(II) acetate (0.169 g). Thereaction mixture was stirred at 45° C. for 5 hours and extracted withdichloromethane. The organic layer was concentrated and the residue wasloaded onto a silica gel column, and eluted with 5-20% ethyl acetate inhexane to give the title compound.

Example 71C methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 71B (274 mg) in dichloroethane (3.5 mL) wasadded EXAMPLE 15F (387 mg) and sodium triacetoxyborohydride (317 mg).The reaction mixture was stirred overnight. Sodium cyanoborohydride(37.6 mg) was added and the resulting mixture stirred overnight. Thereaction was quenched with water and diluted with dichloromethane. Themixture was washed with water extensively and the organic layer wasdried over Na₂SO₄, filtered, and concentrated to provide the titlecompound.

Example 71D2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 3J using EXAMPLE71C in place of EXAMPLE 3I.

Example 71ETrans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 71D and EXAMPLE 9C in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.64 (s, 1H),8.51 (s, 1H), 8.15 (d, 1H), 8.01 (d, 1H), 7.76 (d, 1H), 7.44-7.53 (m,3H), 7.34 (d, 2H), 7.07 (d, 3H), 6.66 (dd, 1H), 6.37 (dd, 1H), 6.20 (d,1H), 3.50-3.70 (m, 5H), 3.04 (s, 4H), 2.55-2.76 (m, 5H), 2.34-2.39 (m,1H), 2.20 (d, 6H), 2.03 (s, 4H), 1.91 (s, 2H), 1.61 (q, 4H), 1.51 (t,2H), 1.36-1.46 (m, 8H).

Example 72Cis-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 15H and 29A in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.69 (s, 1H),11.45 (s, 1H), 8.59 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.79 (dd, 1H),7.54 (d, 1H), 7.47-7.52 (m, 2H), 7.37 (d, 2H), 7.13 (d, 2H), 7.08 (d,1H), 6.68 (dd, 1H), 6.35-6.42 (m, 1H), 6.19 (d, 1H), 4.11 (s, 2H), 3.37(s, 1H), 3.26 (t, 2H), 3.20 (s, 3H), 3.07 (s, 4H), 2.83 (s, 2H), 2.17(d, 6H), 1.81 (dd, 2H), 1.64-1.73 (m, 1H), 1.48 (dd, 2H), 1.23-1.41 (m,4H), 1.18 (s, 6H).

Example 734-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 71D and EXAMPLE 37D in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.68 (s, 1H),8.37 (s, 1H), 7.98-8.11 (m, 2H), 4.38 (d, 2H), 3.74-3.82 (m, 2H),3.54-3.64 (m, 2H), 3.44 (s, 1H), 3.08 (s, 3H), 2.58-2.89 (m, 2H),2.13-2.35 (m, 4H), 2.04 (s, 2H), 1.78-1.93 (m, 4H), 1.57-1.65 (m, 4H),1.52 (t, 2H), 1.36-1.47 (m, 4H).

Example 74Trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 71D and EXAMPLE 34B in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.69 (s, 1H),11.39 (s, 1H), 8.58 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.79 (dd, 1H),7.47-7.55 (m, 3H), 7.34 (d, 2H), 7.07 (d, 3H), 6.68 (dd, 1H), 6.39 (dd,1H), 6.19 (d, 1H), 3.25 (t, 2H), 3.22 (s, 3H), 3.06 (s, 5H), 2.71 (s,2H), 2.21 (s, 6H), 1.94-2.06 (m, 4H), 1.79 (d, 2H), 1.57-1.65 (m, 5H),1.51 (t, 2H), 1.39 (t, 4H), 0.95-1.11 (m, 4H).

Example 754-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 75A methyl5,5-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

The title compound was prepared by substituting4,4-dimethyl-2-methoxycarbonylcyclohexanone for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 3A.

Example 75B methyl2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate

The title compound was prepared by substituting EXAMPLE 75A for EXAMPLE3A in EXAMPLE 3B.

Example 75C (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methanol

The title compound was prepared by substituting EXAMPLE 75B for EXAMPLE3B in EXAMPLE 3C.

Example 75D 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde

To a solution of EXAMPLE 75C (2.8 g) in dichloromethane (50 mL) wasadded Dess-Martin Periodinane (5.68 g). The reaction mixture was stirredat room temperature for 3 hours and diluted with ether and washed with5% NaOH and brine. The organic layer was dried over Na₂SO₄, filtered,and concentrated. The residue was purified by flash chromatography using20% ethyl acetate in hexanes to provide the title compound.

Example 75E methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by replacing4′-chlorobiphenyl-2-carboxaldehyde with EXAMPLE 75D and tert-butylpiperazine-1-carboxylate with EXAMPLE 15F in EXAMPLE 1A.

Example 75F2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 15H by replacingEXAMPLE 15G with EXAMPLE 75E.

Example 75G4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 75F and EXAMPLE 1F in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.69 (s, 1H),11.38 (s, 1H), 8.60 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H),7.47-7.55 (m, 3H), 7.31-7.36 (m, 2H), 7.05-7.13 (m, 3H), 6.68 (dd, 1H),6.39 (dd, 1H), 6.18 (d, 1H), 3.85 (dd, 2H), 3.22-3.31 (m, 4H), 3.07 (s,4H), 2.67-2.78 (m, 2H), 2.19 (s, 6H), 1.82-1.98 (m, 3H), 1.56-1.66 (m,2H), 1.39 (t, 2H), 1.17-1.33 (m, 3H), 0.93 (s, 6H).

Example 764-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 75F and EXAMPLE 36C in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.62 (s, 1H),8.73 (s, 1H), 8.52 (s, 1H), 7.98 (d, 1H), 7.56 (d, 1H), 7.45-7.51 (m,1H), 7.43 (s, 1H), 7.37 (d, 2H), 7.10 (d, 2H), 6.68 (dd, 1H), 6.35 (dd,1H), 6.25 (s, 1H), 4.29 (d, 2H), 3.88 (dd, 2H), 3.12 (d, 4H), 2.21 (s,2H), 2.00-2.11 (m, 1H), 1.95 (s, 2H), 1.64 (dd, 2H), 1.27-1.46 (m, 4H),0.95 (s, 6H)

Example 77 tert-butyl3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}morpholine-4-carboxylateExample 77A tert-butyl3-((2-nitro-4-sulfamoylphenoxy)methyl)morpholine-4-carboxylate

The title compound was prepared as described in EXAMPLE 12A by replacing(1,4-dioxan-2-yl)methanol with tert-butyl3-(hydroxymethyl)morpholine-4-carboxylate.

Example 77B tert-butyl3-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}morpholine-4-carboxylate

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 77A in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 8.36 (s, 1H), 8.01-8.11 (m, 2H),7.47-7.61 (m, 4H), 7.35 (d, 2H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d,1H), 6.20 (s, 1H), 4.41-4.52 (m, 2H), 4.15-4.28 (m, 1H), 3.59-3.95 (m,3H), 3.51 (d, 1H), 3.34-3.43 (m, 1H), 3.10 (s, 5H), 2.84 (s, 2H), 2.28(s, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.20-1.45 (m, 12H), 0.92 (s, 6H).

Example 784-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-3-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 77B (100 mg) in dichloromethane (10 mL) at 0° C. was treatedwith trifluoroacetic acid (5 mL) for 20 minutes. The reaction mixturewas concentrated. The residue was purified by reverse phase HPLC on aC18 column using a gradient of 35-60% acetonitrile in 0.1%trifluoroacetic acid water to give the title compound as atrifluoroacetate salt. The trifluoroacetic acid salt was dissolved indichloromethane (10 mL) and washed with 50% aqueous NaHCO₃. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated to give the titlecompound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.56 (s, 1H), 8.23(d, 1H), 7.94 (d, 1H), 7.90 (dd, 1H), 7.57 (d, 1H), 7.42-7.46 (m, 1H),7.31-7.37 (m, 3H), 7.25 (d, 1H), 7.01-7.09 (m, 2H), 6.64 (dd, 1H),6.29-6.37 (m, 1H), 6.24 (d, 1H), 4.17-4.31 (m, 2H), 3.90-4.05 (m, 1H),3.77-3.85 (m, 1H), 3.45-3.59 (m, 4H), 2.94-3.13 (m, 6H), 2.76 (s, 2H),2.18 (d, 6H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 794-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 71D and EXAMPLE 1F in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.69 (s, 1H),11.38 (s, 1H), 8.60 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.77-7.84 (m,1H), 7.45-7.56 (m, 3H), 7.34 (d, 2H), 7.04-7.13 (m, 3H), 6.68 (dd, 1H),6.39 (d, 1H), 6.19 (d, 1H), 3.85 (dd, 2H), 3.22-3.31 (m, 4H), 3.07 (s,4H), 2.71 (s, 2H), 2.21 (s, 6H), 2.03 (s, 2H), 1.81-1.94 (m, 1H),1.56-1.68 (m, 6H), 1.51 (t, 2H), 1.34-1.45 (m, 4H), 1.20-1.33 (m, 2H).

Example 804-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting1-(methylsulfonyl)piperidin-4-amine for 1-acetylpiperidin-4-amine inEXAMPLE 53B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.67 (br s, 1H),8.57 (d, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.83 (dd, 1H), 7.54-7.46 (m,3H), 7.35 (d, 2H), 7.17 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m,1H), 6.20 (d, 1H), 3.80 (m, 1H), 3.57 (m, 2H), 3.08 (br s, 4H), 2.95(td, 2H), 2.92 (s, 3H), 2.85-2.72 (m, 2H), 2.30-2.10 (m, 6H), 2.07-1.93(m, 4H), 1.70 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 814-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 81A 1,1-Dioxotetrahydro-2H-thiopyran-4-amine

N-Benzyl-1,1-dioxotetrahydro-2H-thiopyran-4-amine (2.00 g) was added toethanol (40 mL) in a pressure bottle. Palladium hydroxide on carbon(0.587 g,) was added and the solution was stirred under 30 psi ofhydrogen at room temperature for 2 hours. The mixture was filteredthrough a nylon membrane and the solvent was removed under vacuum.

Example 81B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 81A for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (br s, 1H), 8.55 (d, 1H), 8.25 (d, 1H),8.03 (d, 1H), 7.86 (dd, 1H), 7.52-7.47 (m, 3H), 7.35 (d, 2H), 7.17 (d,1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.21 (d, 1H), 4.05 (m,1H), 3.22-3.00 (m, 8H), 2.79 (br s, 2H), 2.31-2.11 (m, 10H), 1.96 (br s,2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 82N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE 1G.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.60 (br s, 1H), 8.38 (br s,1H), 7.96 (d, 1H), 7.91 (d, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.46 (t,1H), 7.39-7.35 (m, 3H), 7.07 (d, 2H), 6.67 (dd, 1H), 6.34 (m, 1H), 6.28(d, 1H), 3.31 (br s, 2H), 3.17 (br s, 8H), 2.18 (m, 2H), 1.98 (br s,2H), 1.42 (t, 2H), 0.94 (s, 6H).

Example 834-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 83A3-Nitro-4-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylamino]-benzenesulfonamide

The title compound was prepared by substituting1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride for(tetrahydropyran-4-yl)methylamine in EXAMPLE 6A.

Example 83B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 82A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.66 (br s, 1H), 8.56 (d, 1H), 8.24 (d, 1H),8.04 (d, 1H), 7.81 (dd, 1H), 7.52 (dd, 2H), 7.48 (d, 1H), 7.35 (d, 2H),7.15 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H),3.68 (m, 1H), 3.22 (q, 2H), 3.07 (br s, 4H), 2.90 (m, 2H), 2.75 (br s,2H), 2.29-2.12 (m, 8H), 1.97-1.86 (m, 4H), 1.63 (m, 2H), 1.38 (t, 2H),0.92 (s, 6H).

Example 844-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 84A 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ol

Piperidin-4-ol (7.8 g) and dihydro-2H-pyran-4(3H)-one (5.0 g) weredissolved in titanium(IV) isopropoxide (30 mL) and the reaction wasstirred at room temperature overnight. Methanol (40 mL) was added andthe reaction was cooled to 0° C. Then NaBH₄ (3.8 g) was added inportions over one hour. After 2 hours 1N aqueous NaOH was added,followed by ethyl acetate addition. After filtration through celite thelayers were separated, the aqueous layer extracted with ethyl acetate,and the combined organic layers were dried over Na₂SO₄. The crude waspurified by column chromatography using dichloromethane having 5-10% 7NNH₃ in methanol.

Example 84B5-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 84A for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 36A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 84C5-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 84B for EXAMPLE36B in EXAMPLE 36C.

Example 84D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 84C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.50 (s,1H), 8.60 (d, 1H), 8.37 (d, 1H), 7.90 (d, 1H), 7.60 (d, 1H), 7.42 (dd,1H), 7.35 (d, 2H), 7.25 (d, 1H), 7.04 (d, 2H), 6.63 (dd, 1H), 6.28 (m,1H), 6.24 (d, 1H), 5.30 (br s, 1H), 4.50 (d, 2H), 3.95 (dd, 2H), 3.30(m, 5H), 3.02 (br s, 4H), 2.95 (br s, 2H), 2.24 (br s, 4H), 2.17 (br m,4H), 1.96 (s, 2H), 1.90 (br m, 4H), 1.60 (br m, 2H), 1.39 (t, 2H), 0.93(s, 6H).

Example 854-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 85A5-isopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 36B (0.176 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl(0.041 g), and palladium(II) acetate (0.011 g) were combined in a 10 mLoven-dried flask. Tetrahydrofuran (1 mL) was added and the mixture wasflushed with nitrogen and stirred at ambient temperature for 5 minutes.2-Propylzinc bromide solution (0.5 M in tetrahydrofuran) (1.5 mL) wasadded and stirring was continued under nitrogen overnight. Additional2-2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.041 g) andpalladium(II) acetate (0.011 g) were added. The mixture was flushed withnitrogen and stirred at ambient temperature for 5 minutes. 2-Propylzincbromide solution (0.5 M in tetrahydrofuran) (1.5 mL) was added andstirring was continued under nitrogen for 2.5 days. The reaction mixturewas diluted with ethyl acetate, washed with water and brine, dried(MgSO₄), filtered, concentrated, and chromatographed on silica gel with0 to 3% methanol in CH₂Cl₂ as the eluent. The obtained material waschromatographed on silica gel a second time with 10-40% ethyl acetate inCH₂Cl₂ as the eluent, triturated with diethyl ether and dried undervacuum at 45° C. to give the product.

Example 85B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-isopropyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 85A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.70 (s,1H), 8.49 (m, 1H), 8.04 (d, 1H), 7.90 (m, 1H), 7.57 (m, 1H), 7.52 (t,1H), 7.48 (dd, 1H), 7.34 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.41 (dd,1H), 6.17 (s, 1H), 4.19 (m, 2H), 3.88 (m, 2H), 3.30 (m, 2H), 3.05 (m,5H), 2.77 (s, 2H), 2.21 (s, 4H), 2.14 (s, 2H), 2.03 (m, 1H), 1.95 (s,2H), 1.64 (m, 2H), 1.34 (m, 4H), 1.12 (d, 6H), 0.92 (s, 6H).

Example 86N-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 86A3-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting3,4-difluorobenzenesulfonamide for 4-chloro-3-nitrobenzenesulfonamideand (tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-aminedihydrochloride in EXAMPLE 6A.

Example 86B3-chloro-5-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 86A for EXAMPLE52B in EXAMPLE 52C.

Example 86CN-({3-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 86B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.72 (s,1H), 11.20 (s, 1H), 8.08 (d, 1H), 7.61 (m, 2H), 7.50 (m, 3H), 7.34 (d,2H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.42 (dd, 1H), 6.16 (d, 1H), 6.09 (m,1H), 3.81 (dd, 2H), 3.25 (m, 4H), 3.07 (m, 4H), 2.76 (s, 2H), 2.18 (m,6H), 1.95 (s, 2H), 1.72 (m, 1H), 1.53 (d, 2H), 1.38 (t, 2H), 1.16 (m,2H), 0.92 (s, 6H).

Example 874-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide Example 87A methyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate

The title compound was prepared by substituting 5-hydroxyindole forEXAMPLE 3G in EXAMPLE 3H.

Example 87B methyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 87A for EXAMPLE3H in EXAMPLE 3I.

Example 87C2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 87B for EXAMPLE3I in EXAMPLE 3J.

Example 87D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE1E in EXAMPLE 1G, except here the crude was purified by preparative HPLCusing a 250×50 mm C18 column and eluting with 20-100% CH₃CN vs. 0.1%trifluoroacetic acid in water, giving the product as a trifluoroacetatesalt. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.40 (br s, 1H), 11.17(s, 1H), 9.50 (v br s, 1H), 8.61 (t, 1H), 8.57 (d, 1H), 7.77 (dd, 1H),7.70 (br s, 1H), 7.50 (m, 5H), 7.36 (m, 5H), 7.10 (s, 1H), 7.08 (d, 1H),6.83 (dd, 1H), 6.69 (dd, 1H), 6.37 (m, 1H), 6.21 (d, 1H), 4.30 (br s,1H), 3.84 (dd, 2H), 3.70 (br s, 1H), 3.30 (m, 6H), 3.20, 2.95, 2.80 (allbr s, total 6H), 1.86 (m, 1H), 1.60 (m, 2H), 1.25 (m, 2H).

Example 884-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE1E and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G, except here the crudewas purified by preparative HPLC using a 250×50 mm C18 column andeluting with 20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water,giving the product as a trifluoroacetate salt. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.40 (br s, 1H), 11.19 (s, 1H), 9.60 (v br s,1H), 8.69 (t, 1H), 8.60 (d, 1H), 7.83 (dd, 1H), 7.65 (br s, 1H), 7.50(m, 5H), 7.38 (m, 5H), 7.12 (m, 2H), 6.83 (dd, 1H), 6.69 (dd, 1H), 6.39(m, 1H), 6.20 (d, 1H), 4.38 (br s, 1H), 4.00 (m, 2H), 3.80 (br s, 1H),3.40 (m, 4H), 3.30-2.80 (envelope, 10H), 3.20 (m, 4H), 1.96 (m, 2H).

Example 894-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 87C for EXAMPLE 1E andEXAMPLE 3M for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.15 (s, 1H), 8.56 (d, 1H), 8.20 (d, 1H), 7.84(dd, 1H), 7.52 (d, 1H), 7.39-7.31 (m, 4H), 7.12 (d, 2H), 7.04 (d, 2H),6.84 (dd, 1H), 6.65 (dd, 1H), 6.38 (t, 1H), 6.14 (d, 1H), 3.94 (m, 2H),3.84 (m, 1H), 3.02 (m, 8H), 2.79 (m, 3H), 2.72 (s, 2H), 2.20-2.02 (m,8H), 1.85 (m, 6H), 1.60 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 904-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE1E and EXAMPLE 4A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.08 (s, 1H), 8.51 (d, 1H), 8.13 (d, 1H), 7.78(dd, 1H), 7.52 (d, 1H), 7.37-7.31 (m, 4H), 7.06-7.00 (m, 4H), 6.79 (dd,1H), 6.59 (dd, 1H), 6.35 (t, 1H), 6.14 (d, 1H), 3.73 (m, 1H), 3.05-2.95(m, 6H), 2.71 (s, 2H), 2.60 (m, 2H), 2.48 (s, 3H), 2.16 (m, 6H), 2.01(m, 2H), 1.95 (s, 2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 914-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 6A for EXAMPLE11B and EXAMPLE 87C for EXAMPLE 3J in EXAMPLE 11D. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 9.18 (s, 1H), 8.53 (d, 1H), 7.84(dd, 1H), 7.56 (d, 1H), 7.51 (d, 1H), 7.39 (m, 2H), 7.33 (d, 2H), 7.12(d, 1H), 7.03 (d, 2H), 6.84 (dd, 1H), 6.62 (dd, 1H), 6.38 (m, 1H), 6.13(d, 1H), 3.00 (m, 4H), 2.90 (m, 4H), 2.71 (s, 2H), 2.33 (s, 3H), 2.15(m, 6H), 1.94 (s, 2H), 1.37 (t, 2H), 0.92 (s, 6H).

Example 924-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 87C and EXAMPLE 12A in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H),8.39 (d, 1H), 8.06 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 3H), 7.34 (d,2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s,1H), 6.15 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd, 1H),3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.05 (s, 4H),2.78 (s, 2H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38 (t, 2H),0.92 (s, 6H).

Example 934-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE3J and EXAMPLE 16A for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.18 (d, 1H), 7.92 (dd, 1H), 7.49(d, 1H), 7.40 (m, 2H), 7.33 (d, 2H), 7.26 (m, 1H), 7.17 (d, 1H), 7.04(m, 3H), 6.86 (dd, 1H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.14 (d, 1H), 3.51(m, 4H), 3.28 (s, 3H), 3.03 (s, 4H), 2.74 (s, 2H), 2.16 (m, 6H), 1.95(s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 944-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 87C for EXAMPLE3J and EXAMPLE 17A for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.19 (d, 1H), 7.90 (dd, 1H), 7.53(d, 1H), 7.40 (m, 4H), 7.33 (t, 1H), 7.17 (d, 1H), 7.07 (m, 3H), 6.86(dd, 1H), 6.70 (dd, 1H), 6.41 (s, 1H), 6.21 (d, 1H), 3.84 (dd, 2H), 3.59(m, 2H), 3.25 (m, 6H), 3.00 (m, 2H), 2.74 (s, 2H), 2.54 (m, 2H), 2.18(s, 2H), 2.01 (s, 2H), 1.83 (m, 1H), 1.54 (m, 2H), 1.45 (t, 2H), 1.23(m, 2H), 0.94 (s, 6H).

Example 954-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 95A 1-(1,3-difluoropropan-2-yl)piperidin-4-amine

Tert-butyl piperidin-4-ylcarbamate (0.212 g), 1,3-difluoropropan-2-one(0.149 g) and sodium triacetoxyborohydride (0.337 g) were stirredtogether in dichloroethane at room temperature. After stirring overnightthe reaction was quenched with water (10 mL) and extracted intodichloromethane (2×20 mL). The organic layer was dried over magnesiumsulfate, filtered, and concentrated. The residue was treated withhydrogen chloride (4.0M in dioxane, 1.323 ml) for 1 hour to give thetitle compound as the HCl salt after concentration.

Example 95B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 95A (0.057 g) and EXAMPLE 53A (0.162 g) were suspended indioxane (3 mL) and heated to 105° C. overnight. The reaction wasconcentrated, loaded onto silica gel (GRACERESOLV 12 g) and eluted witha gradient of 0.5% to 4% methanol/dichloromethane. The productcontaining fractions were concentrated and loaded onto C18 (SF25-75 ganalogix column) and eluted using a gradient of 30% to 60%acetonitrile/water. The product was partitioned between dichloromethane(20 mL) and saturated aqueous NaHCO₃ solution (20 mL). The organic layerwas dried over magnesium sulfate, filtered, and concentrated to give thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ 10.10 (s, 1H), 8.88 (d, 2H),8.45 (d, 1H), 8.20 (s, 1H), 8.18-8.09 (m, 1H), 7.95 (d, 1H), 7.68 (d,1H), 7.44 (s, 1H), 7.23-7.19 (m, 1H), 6.91 (d, 3H), 6.53 (d, 2H), 5.98(d, 1H), 4.64 (dd, 4H), 3.68-3.50 (m, 1H), 3.01 (d, 6H), 2.72 (d, 4H),2.19 (s, 11H), 1.69 (s, 2H), 1.41 (s, 2H), 0.94 (s, 6H).

Example 96N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 96A5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 37C for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 96BN-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 96A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.52 (s, 1H), 8.41 (s, 1H), 8.03 (d, 1H), 7.56 (d, 1H), 7.50 (m,2H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (m, 1H), 6.22 (s,1H), 4.50 (d, 2H), 3.78 (m, 2H), 3.60 (m, 2H), 3.12 (v br s, 4H), 2.93(v br s, 2H), 2.38 (v br s, 4H), 2.17 (br m, 2H), 1.96 (s, 2H), 1.86 (m,4H), 1.40 (t, 2H), 0.93 (s, 6H).

Example 974-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 97A tert-butyl4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate

The title compound was prepared by substituting tert-butyl4-aminopiperidine-1-carboxylate for 4-methylpiperazin-1-aminedihydrochloride in EXAMPLE 6A.

Example 97B 3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide

Tert-butyl 4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylatewas dissolved in dichloromethane (3 mL) and treated with 1N HCl in ether(4 mL). The reaction was stirred overnight then concentrated to give thetitle compound.

Example 97C4-(1-(2,2-difluoroethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide

3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide hydrochloride (0.100g), 1,1-difluoro-2-iodoethane (0.063 mL) and diisopropylamine (0.156 mL)were stirred together in N,N-dimethylformamide (3 ml) and heated to 85°C. The reaction was diluted with dichloromethane (50 mL) and washed withwater (50 mL), brine (50 mL), dried over magnesium sulfate, filtered,and concentrated. The residue was loaded onto silica gel (GRACERESOLV 12g) and eluted using a gradient of 0.5% methanol/dichloromethane to 3%methanol/dichloromethane over 30 minutes to give the title compound.

Example 97D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-difluoroethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 97B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.54-11.27 (m, 1H), 8.55 (d,1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.81 (d, 1H), 7.50 (dd, 3H), 7.34 (d,2H), 7.13 (d, 1H), 7.04 (d, 2H), 6.68 (d, 1H), 6.38 (dd, 1H), 6.15 (dt,2H), 3.64 (s, 1H), 3.07 (s, 4H), 2.79 (ddd, 6H), 2.41 (t, 2H), 2.17 (d,6H), 1.92 (d, 4H), 1.61 (d, 2H), 1.38 (s, 2H), 0.92 (s, 6H).

Example 984-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 53B by replacing1-acetylpiperidin-4-amine with 4-amino-1-cyclopropylpiperidine. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 8.54 (d, 1H), 8.22 (d,1H), 8.02 (d, 1H), 7.80 (dd, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.11 (d,1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.19 (d, 1H), 3.69 (m,1H), 3.06 (m, 4H), 2.92 (m, 2H), 2.74 (s, 2H), 2.23 (m, 7H), 1.93 (m,5H), 1.77 (m, 1H), 1.55 (m, 3H), 1.38 (t, 2H), 0.92 (s, 6H), 0.43 (m,4H).

Example 994-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 53B by replacing1-acetylpiperidin-4-amine with 1-(4-morpholino)cyclohexanemethylamine.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.70 (s, 1H), 9.06 (s, 1H),8.59 (d, 1H), 8.06 (d, 1H), 7.83 (dd, 1H), 7.57 (d, 1H), 7.50 (m, 2H),7.34 (m, 3H), 7.19 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.41 (dd, 1H),6.17 (d, 1H), 3.56 (m, 6H), 3.44 (m, 2H), 3.07 (m, 5H), 2.57 (m, 5H),2.24 (m, 6H), 1.95 (s, 3H), 1.45 (m, 6H), 1.23 (m, 3H), 0.92 (s, 6H).

Example 100Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 100A Trans-tert-butyl-4-(dicyclopropylamino)cyclohexylcarbamate

A suspension of trans-tert-butyl-4-aminocyclohexylcarbamate (1 g),molecular sieves 3A (1 g), acetic acid (2.67 ml),(1-ethoxycyclopropoxy)trimethylsilane (3.74 ml) and sodiumcyanoborohydride (0.880 g) in dry methanol (10 ml) was heated at refluxfor 3 hours. The insolubles were filtered off, the resulting solutionwas basified with aqueous NaOH (6 M) to pH 14, and extracted with ether.The combined extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flashchromatography (silica gel 80 g, 30-100% acetone/hexanes) to provide thetitle compound.

Example 100B (trans)-N¹,N¹-dicyclopropylcyclohexane-1,4-diaminebis(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 100A for EXAMPLE39A in EXAMPLE 39B.

Example 100CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A suspension of EXAMPLE 53A (0.14 g), EXAMPLE 100B (0.112 g) andN,N-diisopropylethylamine (0.310 mL) in dioxane (10 mL) was stirred for3 days at 100° C. The product was concentrated and purified by RPHPLC(C8, 30%-100% CH₃CN/water/0.1% trifluoroacetic acid). ¹H NMR (500MHz, pyridine-d₅) δ 13.07 (s, 1H), 9.28 (d, 1H), 8.41-8.45 (m, 2H), 8.37(d, 1H), 8.12 (d, 1H), 7.67 (d, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 7.01(d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.48-6.51 (m, 1H), 3.43 (ddd, 1H),3.03-3.09 (m, 4H), 2.72-2.79 (m, 3H), 2.22-2.28 (m, 2H), 2.11-2.16 (m,4H), 2.10 (s, 2H), 2.00-2.05 (m, 2H), 1.97 (s, 2H), 1.89 (s, 1H), 1.86(s, 3H), 1.62-1.71 (m, 2H), 1.39 (t, 2H), 1.19-1.29 (m, 2H), 0.93 (s,6H), 0.48 (d, 8H).

Example 1014-(4-{[2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 101A Ethyl 2-hydroxy-6,6-dimethylcyclohex-1-enecarboxylate

Into a 500 mL flame dried round-bottomed flask was added copper(I)iodide (18 g) in ether (200 mL) to give a suspension. After cooling to−5° C., methyllithium (120 mL, 1.6M in ether) was added dropwise. Afterstirring at −5° C. for 1 hour, 3-methylcyclohex-2-enone (5.15 mL) in 15ml ether was added dropwise, and the mixture was stirred at −5° C. for 1hour. After cooling to −78° C., hexamethylphosphoramide (60 mL) wasadded dropwise. Ethyl carbonocyanidate (23.74 mL) was added. Afterstirring at −78° C. for 20 minutes, the mixture was warmed up to roomtemperature, and stirred for 1 hour. The mixture was poured into coldwater, and the layers were separated. The aqueous layer was extractedwith ether (3×20 mL). The combined organic layers were washed withsaturated aqueous NH₄Cl (3×20 mL), dried over Na₂SO₄, filtered, anddried under vacuum. The crude product was added to a silica gel columnand purified by eluting with 0-10% ethyl acetate in hexane.

Example 101B Ethyl6,6-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

Into a 500 mL round-bottomed flask was added hexane-washed sodiumhydride (0.5 g) in dichloromethane (100 mL) to give a suspension. Aftercooling to −5° C., EXAMPLE 101A (2.0 g) was added. After stirring at −5°C. for 30 minutes, the mixture was cooled to −78° C.Trifluoromethanesulfonic anhydride (2.2 mL) was added. The mixture waswarmed to room temperature and stirred overnight. Water was added slowlyto the mixture, the aqueous layer was then extracted by dichloromethane(2×20 mL). The combined organic layers were washed with saturated NH₄Cland brine, dried over Na₂SO₄, filtered, and concentrated.

Example 101C ethyl2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-enecarboxylate

Into a 25 mL microwave tube was added EXAMPLE 101B (2.9 g),4-chlorophenylboronic acid (2.2 g), andtetrakis(triphenylphosphine)palladium (0.05 g) in1,2-dimethoxyethane/methanol (2:1, 10 mL) to give a solution. Cesiumfluoride (4 g) was then added. The reaction mixture was stirred at 150°C. under (100W) in a Biotage Initiator microwave reactor for 30 minutes.After removing the solvents, water was added, and the mixture wasextracted with ethyl acetate (2×). The combined organic layers weredried by MgSO₄. After filtering, the crude product was purified byreverse phase chromatography eluting with 50-100% acetonitrile/waterwith 0.1% trifluoroacetic acid.

Example 101D (2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-enyl)methanol

In a 100 mL round-bottomed flask was placed lithium aluminum hydride (1g) in ether (20 mL) to give a suspension. EXAMPLE 101C (1 g) dissolvedin ether (5 mL) was added slowly by syringe. The mixture was stirred atroom temperature overnight. After cooling to 0° C., the reaction wasquenched by water. Ether (2×10 mL) was used to extract the product. Thecrude product was purified by flash chromatography on silica by elutingwith 0-15% ethyl acetate in hexane.

Example 101E Methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a 0° C. solution of EXAMPLE 101D (0.43 g) in dichloromethane (5 mL)was added triethylamine (1 mL). Methanesulfonyl chloride (0.134 mL) wasthen added slowly. After 5 minutes, EXAMPLE 15F (0.61 g) was added. Themixture was stirred at room temperature overnight. The crude product waspurified by flash chromatography on silica with 0 to 25% ethyl acetatein hexanes to provide the title compound.

Example 101F2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

In a 5 mL microwave tube was added lithium hydroxide hydrate (15 mg) andEXAMPLE 101E (45 mg) in dioxane/water (2:1) (2 mL) to give a suspension.The mixture was heated to 130° C. in a Biotage Initiator microwavereactor for 20 minutes. After cooling and neutralization by HCl, thecrude product was added to a Prep HPLC column and was eluted with 20-80%acetonitrile/water with 0.1% trifluoroacetic acid.

Example 101G4-(4-{[2-(4-chlorophenyl)-6,6-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 101F for EXAMPLE3J and EXAMPLE 1F for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 11.47 (s, 1H), 8.58 (m, 2H), 8.03(m, 1H), 7.79 (m, 1H), 7.51 (m, 3H), 7.31 (d, 2H), 7.10 (m, 1H), 7.02(d, 2H), 6.65 (m, 1H), 6.39 (m, 1H), 6.15 (m, 1H), 3.85 (m, 2H), 3.27(m, 4H), 2.97 (m, 4H), 2.76 (s, 2H), 2.14 (m, 6H), 1.70 (m, 2H), 1.61(m, 2H), 1.44 (m, 2H), 1.26 (m, 3H), 1.16 (m, 6H)

Example 102N-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 102A (4-ethylmorpholin-3-yl)methanol

Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) inN,N-dimethylformamide was treated with K₂CO₃ (1.1 g) overnight. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was dried over Na₂SO₄, filtered, andconcentrated to provide the title compound.

Example 102B5-bromo-6-((4-ethylmorpholin-3-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared as described in EXAMPLE 12A by replacing4-fluoro-3-nitrobenzenesulfonamide and (1,4-dioxan-2-yl)methanol with5-bromo-6-fluoropyridine-3-sulfonamide and EXAMPLE 102A, respectively.

Example 102CN-({5-bromo-6-[(4-ethylmorpholin-3-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 102B in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.62 (s, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 8.00(d, 1H), 7.55 (d, 1H), 7.45-7.50 (m, 2H), 7.35 (d, 2H), 7.05 (d, 2H),6.66 (dd, 1H), 6.37 (s, 1H), 6.21 (d, 1H), 4.58 (dd, 1H), 4.39-4.50 (m,1H), 3.78-3.90 (m, 1H), 3.67-3.77 (m, 1H), 3.50-3.65 (m, 2H), 3.08 (s,4H), 2.59-3.00 (m, 4H), 2.20-2.39 (m, 2H), 2.15 (s, 2H), 1.96 (s, 2H),1.39 (t, 2H), 0.99-1.11 (m, 3H), 0.93 (s, 6H)

Example 1034-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 103A4-((4-ethylmorpholin-3-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 12A by replacing(1,4-dioxan-2-yl)methanol with EXAMPLE 102A.

Example 103B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 103A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 8.33 (s, 1H), 7.99-8.06 (m, 2H),7.47-7.57 (m, 3H), 7.45 (d, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd,1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.42 (dd, 1H), 4.23 (dd, 1H), 3.81 (d,1H), 3.69 (d, 1H), 3.49-3.63 (m, 2H), 3.08 (s, 4H), 2.92 (s, 1H), 2.81(s, 4H), 2.54 (s, 1H), 2.25 (s, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.39(t, 2H), 1.00 (t, 3H), 0.92 (s, 6H)

Example 1044-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 78 (20 mg) and dihydro-2H-pyran-4(3H)-one (10 mg) indichloroethane (2 mL) was treated with NaCNBH₃ (9.74 mg) overnight.Additional dihydro-2H-pyran-4(3H)-one (20 mg) and titanium (IV)isopropoxide (0.05 mL) were added. The resulting mixture was stirred atroom temperature overnight and concentrated. The residue was purified byreverse phase HPLC on a C18 column using a gradient of 35-60%acetonitrile in 0.1% trifluoroacetic acid water to give the titlecompound as a trifluoroacetate salt. The trifluoroacetic acid salt wasdissolved in dichloromethane (6 mL) and washed with 50% aqueous NaHCO₃.The organic layer was dried over anhydrous Na₂SO₄ and concentrated togive the title compound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.68(s, 1H), 8.35 (s, 1H), 8.04 (s, 2H), 7.44-7.58 (m, 4H), 7.35 (d, 2H),7.04 (d, 2H), 6.67 (dd, 1H), 6.40 (s, 1H), 6.20 (s, 1H), 4.44 (s, 1H),4.28 (s, 1H), 3.85 (d, 2H), 3.71 (d, 1H), 3.61 (s, 3H), 3.20-3.29 (m,2H), 3.08 (s, 5H), 2.54-2.96 (m, 5H), 2.06-2.42 (m, 5H), 1.96 (s, 2H),1.77 (d, 1H), 1.53-1.66 (m, 1H), 1.29-1.51 (m, 4H), 0.92 (s, 6H)

Example 1054-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 105A (S)-tert-butyl1-(tetrahydro-2H-pyran-4-yl)piperidin-3-ylcarbamate

The title compound was prepared by substituting (S)-tert-butylpiperidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate anddihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde inEXAMPLE 1A.

Example 105B (S)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-amine

The title compound was prepared by substituting EXAMPLE 105A for EXAMPLE1A in EXAMPLE 1B.

Example 105C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 105B for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.68 (br s, 1H), 8.54 (br s, 1H), 8.02 (d, 1H),7.77 (m, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.03 (m, 3H), 6.67 (dd, 1H),6.38 (m, 1H), 6.19 (d, 1H), 3.98 (m, 2H), 3.90 (m, 2H), 3.52 (m, 2H),3.09 (s, 2H), 3.05 (m, 4H), 2.77 (m, 2H), 2.60 (m, 2H), 2.16 (m, 6H),1.95 (m, 2H), 1.65 (m, 5H), 1.50 (m, 3H), 1.38 (m, 2H), 0.94 (s, 6H).

Example 1064-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 106 A5-Bromo-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting(tetrahydro-2H-pyran-4-yl)methanamine for EXAMPLE 3L in EXAMPLE 61A.

Example 106B5-cyano-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 106A for EXAMPLE36B in EXAMPLE 36C.

Example 106C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 106B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.62 (s,1H), 8.55 (s, 1H), 8.14 (s, 1H), 8.01 (d, 1H), 7.87 (s, 1H), 7.56 (d,1H), 7.48 (d, 2H), 7.34 (d, 2H), 7.04 (d, 2H), 6.64 (m, 1H), 6.37 (s,1H), 6.19 (d, 1H), 3.81 (dd, 2H), 3.25 (m, 4H), 3.04 (s, 4H), 2.74 (s,2H), 2.17 (m, 6H), 1.95 (s, 2H), 1.87 (m, 1H), 1.53 (m, 2H), 1.37 (t,2H), 1.18 (m, 2H), 0.91 (s, 6H).

Example 107Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 107A3-nitro-4-(4-aminothiomorpholine-1,1-dioxide)benzenesulfonamide

The title compound was prepared by substituting4-aminothiomorpholine-1,1-dioxide for (tetrahydropyran-4-yl)methylaminein EXAMPLE 1F.

Example 107BTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 107A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.64 (s,1H), 9.58 (s, 1H), 8.50 (s, 1H), 8.02 (d, 1H), 7.78 (m, 2H), 7.50 (m,3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.38 (s, 1H), 6.19 (d,1H), 3.48 (m, 4H), 3.23 (m, 4H), 3.05 (s, 4H), 2.73 (d, 2H), 2.16 (m,6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 108N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 108A4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting4-(aminomethyl)tetrahydro-2H-pyran-4-amine for(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 108BN-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 108A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.55 (s,1H), 8.45 (s, 2H), 7.95 (d, 1H), 7.75-7.77 (m, 1H), 7.57 (d, 2H), 7.44(s, 1H), 7.34 (d, 2H), 7.09 (d, J=8.85 Hz, 1H), 7.05 (d, 2H), 6.69 (dd,1H), 6.33 (d, 1H), 6.22 (d, 1H), 3.59-3.71 (m, 6H), 3.01 (s, 4H), 2.73(s, 2H), 2.15-2.19 (m, 6H), 1.95 (s, 2H), 1.71-1.74 (m, 2H), 1.59-1.61(m, 1H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 109Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 109ATrans-5-bromo-6-(4-morpholinocyclohexyloxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 9B for EXAMPLE3L in EXAMPLE 61A.

Example 109BTrans-5-cyano-6-(4-morpholinocyclohexylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 109A for EXAMPLE36B in EXAMPLE 36C.

Example 109CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 109B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.59 (s,1H), 8.56 (d, 1H), 8.13 (s, 1H), 8.00 (d, 1H), 7.55 (d, 1H), 7.47 (m,2H), 7.34 (d, 2H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.36 (d, 1H), 6.19 (d,1H), 4.00 (m, 1H), 3.65 (m, 4H), 3.28 (m, 4H), 3.03 (m, 4H), 2.73 (m,4H), 2.16 (m, 6H), 1.90 (m, 6H), 1.40 (m, 6H), 0.93 (s, 6H).

Example 1104-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 52B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.71 (s,1H), 11.23 (s, 1H), 8.08 (d, 1H), 7.91 (d, 1H), 7.74 (dd, 1H), 7.60 (d,1H), 7.52 (m, 2H), 7.34 (m, 2H), 7.16 (s, 1H), 7.04 (m, 2H), 6.83 (d,1H), 6.68 (dd, 1H), 6.43 (dd, 1H), 6.16 (d, 1H), 3.83 (dd, 2H), 3.23 (m,2H), 3.12 (t, 2H), 3.06 (m, 4H), 2.73 (m, 2H), 2.15 (m, 6H), 1.95 (s,2H), 1.82 (m, 1H), 1.58 (m, 2H), 1.38 (m, 2H), 1.18 (m, 2H), 0.92 (s,6H).

Example 1114-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S,3R)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 111A benzyl(1S,3R)-3-(tert-butoxycarbonylamino)cyclopentylcarbamate

(1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (1.03g), diphenylphosphoryl azide (DPPA, 1.00 mL), triethylamine (0.929 mL),and benzyl alcohol (0.931 mL) were combined in toluene (10 mL) andstirred at 100° C. for 24 hours. The solution was cooled andchromatographed on silica gel using 10% ethyl acetate/hexanes to givethe pure product.

Example 111B benzyl (1S,3R)-3-aminocyclopentylcarbamate

The title compound was prepared by substituting EXAMPLE 111A for EXAMPLE1A in EXAMPLE 1B.

Example 111C benzyl (1S,3R)-3-morpholinocyclopentylcarbamate

A solution of EXAMPLE 111B (400 mg), 1-bromo-2-(2-bromoethoxy)ethane(0.246 mL), and triethylamine (0.595 mL) in N,N-dimethylformamide (6 mL)was stirred at 70° C. for 24 hours. The solution was cooled and pouredinto ethyl acetate (200 mL). The solution was extracted with 3× water,washed with brine, concentrated, and chromatographed on silica gel using10% methanol/ethyl acetate to give the pure product.

Example 111D (1S,3R)-3-morpholinocyclopentanamine

EXAMPLE 111C (300 mg) and ethanol (20 ml) were added to wet 20%Pd(OH)₂—C (60.0 mg) in a 50 mL pressure bottle and stirred for 8 hoursat 30 psi. The mixture was filtered through a nylon membrane andcondensed to give the product.

Example 111E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S,3R)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 111D for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR(dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 8.45 (d, 1H), 8.28 (dd, 1H),7.97 (d, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 7.44 (d, 2H), 7.35 (d, 2H),7.05 (d, 2H), 6.92 (dd, 1H), 6.85 (dd, 1H), 6.33 (s, 1H), 6.22 (s, 1H),4.08 (m, 1H), 3.60 (br s, 4H), 3.06 (br s, 4H), 2.73 (br s, 3H), 2.48(m, 4H), 2.28 (m, 1H), 2.18 (m, 6H), 2.07 (m, 1H), 1.95 (s, 2H), 1.79(m, 2H), 1.63 (m, 2H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 1124-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,3S)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 112A tert-butyl (1R,3S)-3-aminocyclopentylcarbamate

The title compound was prepared by substituting EXAMPLE 111A for EXAMPLE111C in EXAMPLE 111D.

Example 112B tert-butyl (1R,3S)-3-morpholinocyclopentylcarbamate

The title compound was prepared by substituting EXAMPLE 112A for EXAMPLE111B in EXAMPLE 111C.

Example 112C (1R,3S)-3-morpholinocyclopentanamine

The title compound was prepared by substituting EXAMPLE 112B for EXAMPLE1A in EXAMPLE 1B.

Example 112D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,3S)-3-morpholin-4-ylcyclopentyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 112C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR(dimethylsulfoxide-d₆) δ 11.35 (s, 1H), 8.51 (d, 1H), 8.44 (dd, 1H),8.00 (d, 1H), 7.77 (d, 1H), 7.50 (d, 1H), 7.48 (s, 2H), 7.34 (d, 2H),7.04 (d, 2H), 7.02 (dd, 1H), 6.67 (dd, 1H), 6.37 (dd, 1H), 6.21 (d, 1H),4.11 (m, 1H), 3.61 (br s, 4H), 3.06 (br s, 4H), 2.73 (br s, 3H), 2.50(m, 4H), 2.28 (m, 1H), 2.18 (m, 6H), 2.06 (m, 1H), 1.95 (s, 2H), 1.77(m, 2H), 1.66 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1134-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 113A tert-butyl2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting tert-butyl2-(aminomethyl)morpholine-4-carboxylate for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 113B tert-butyl2-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 113A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G, with the exception thatthe product was purified on a silica gel column eluted with 4% methanolin dichloromethane.

Example 113C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(morpholin-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 113B for EXAMPLE66B in EXAMPLE 66C. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.60 (s,1H), 8.55 (br, s, 1H), 8.51 (s, 1H), 8.00 (d, 1H), 7.80 (d, 1H), 7.52(d, 1H), 7.49-7.46 (m, 2H), 7.34 (d, 2H), 7.07 (d, 1H), 7.04 (d, 2H),6.66 (dd, 1H), 6.36 (s, 1H), 6.20 (d, 1H), 4.00 (dd, 1H), 3.91 (m, 1H),3.70 (t, 1H), 3.60 (m, 1H), 3.58 (m, 1H), 3.32 (m, 1H), 3.16 (d, 1H),3.05 (m, 4H), 2.98 (td, 1H), 2.86 (t, 1H), 2.73 (s, 2H), 2.20-2.12 (m,6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1144-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 114A3-nitro-4-((tetrahydrofuran-3-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting3-aminomethyl-tetrahydrofuran for (tetrahydropyran-4-yl)methylamine inEXAMPLE 1F.

Example 114B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 114A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.68 (s,1H), 11.42 (bs, 1H), 8.63 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.80 (dd,1H), 7.53-7.48 (m, 3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04 (d, 2H), 6.68(dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 3.82-3.79 (m, 1H), 3.71 (t, 1H),3.62 (dd, 1H), 3.50 (dd, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 3.07 (m, 4H),2.76 (s, 2H), 2.58 (m, 1H), 2.25-2.00 (m, 6H), 1.98 (m, 1H), 1.95 (s,2H), 1.65 (m, 1H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1154-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[cis-3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 115A Cis-tert-butyl1-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate

The title compound was prepared as a racemate of the cis diastereomer bysubstituting tert-butyl piperidin-4-ylcarbamate for piperidin-4-ol and3-fluorodihydro-2H-pyran-4(3H)-one (prepared by the method described inUS2005/0101628A¹) for dihydro-2H-pyran-4(3H)-one) in EXAMPLE 84A.

Example 115B Cis-1-(3-fluorotetrahydro-2H-pyran-4-yl)piperidin-4-amine

EXAMPLE 115A (0.29 g) was dissolved in CH₂Cl₂ (9 mL), then 4NHCl indioxane (4 mL) was added and the reaction stirred at room temperaturefor 16 hours. The reaction was diluted with CH₂Cl₂ (30 mL), then 4Naqueous NaOH (5 mL) was added. After shaking and separating the layersthe aqueous layer was saturated with solid NaCl and extracted with moreCH₂Cl₂ (10 mL). The combined organic layers were dried over Na₂SO₄.After filtration and concentration the amine was used with no furtherpurification.

Example 115C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[cis-3-fluorotetrahydro-2H-pyran-4-yl]piperidin-4-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 115B for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.64 (s, 1H), 8.54 (d, 1H), 8.43 (br d, 1H),8.03 (d, 1H), 7.80 (dd, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.11 (d, 1H),7.05 (d, 2H), 6.66 (dd, 1H), 6.38 (m, 1H), 6.20 (d, 1H), 4.92 (d, 1H),3.95 (m, 2H), 3.70 (v br m, 1H), 3.50, 3.40, 3.30 (all m, total 5H),3.05, 3.00 (both v br m, total 5H), 2.74 (s, 2H), 2.55 (v br m, 1H),2.18 (br m, 6H), 1.95 (m, 4H), 1.88 (ddd, 1H), 1.63 (v br m, 3H), 1.38(t, 2H), 0.92 (s, 6H).

Example 1164-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 116A 1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine

Tert-butyl azetidin-3-ylcarbamate (0.46 g), dihydro-2H-pyran-4(3H)-one(0.29 g) and sodium triacetoxyborohydride (0.85 g) were stirred togetherin dichloromethane (5 mL) overnight. The reaction was poured intodichloromethane (50 mL) and saturated aqueous NaHCO₃ solution (25 mL).The organic layer was separated, washed with brine (25 mL), dried overNa₂SO₄, filtered, and concentrated. Silica gel chromatography(GRACERESOLV 12 g) eluting with a gradient of 0.75% to 7.5%methanol/dichloromethane over 20 minutes gave the Boc-protectedintermediate. Treatment with HCl (4.0M in dioxane, 2 mL) and methanol (1mL) for 1 hour gave the title compound after concentration as the di-HClsalt.

Example 116B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A suspension of2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazinol-yl)benzamide(0.180 g), 1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine (0.078 g), andtriethylamine (0.159 mL) in dioxane (2 mL) was degassed with nitrogenfor 30 seconds then sealed. The reaction was heated to 110° C. Afterstirring for 16 hours, more triethylamine (10 equivalents total) anddimethylsulfoxide (1 mL) were added and the reaction stirred for anadditional 18 hours at 110° C. The reaction was cooled, diluted withwater (50 mL) and extracted with dichloromethane (2×150 mL). The organiclayer was dried over magnesium sulfate, filtered and concentrated.Silica gel chromatography (GRACERESOLV 12 g) eluting with a gradient of0.75% to 7.5% methanol/dichloromethane (Flow=36 mL/minutes) gave thetitle compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.59 (s, 1H),8.49 (d, 1H), 8.40 (s, 1H), 7.97 (d, 1H), 7.77 (s, 1H), 7.47 (dd, 3H),7.34 (d, 2H), 7.04 (d, 2H), 6.90-6.78 (m, 1H), 6.65 (d, 1H), 6.35 (s,1H), 6.21 (s, 1H), 4.47-4.23 (m, 1H), 3.83 (s, 3H), 3.05 (s, 6H), 2.73(s, 2H), 2.18 (s, 8H), 1.95 (s, 2H), 1.68 (s, 2H), 1.38 (s, 2H), 1.24(s, 4H), 0.92 (s, 6H).

Example 1174-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 117A 1-(tetrahydrofuran-3-yl)azetidin-3-amine

Tert-butyl azetidin-3-ylcarbamate (0.550 g), dihydrofuran-3(2H)-one(0.412 g) and sodium triacetoxyborohydride (1.015 g) were stirredtogether in dichloromethane (5 mL). After stirring overnight, thereaction was poured into saturated aqueous NaHCO₃ solution (25 mL) andextracted with dichloromethane (50 mL). The organic layer was washedwith brine (25 mL), dried over magnesium sulfate, filtered, andconcentrated. Silica gel chromatography (GRACERESOLV 12 g) eluting witha gradient of 0.5% to 7.5% methanol/dichloromethane over 30 minutes gavetert-butyl 1-(tetrahydrofuran-3-yl)azetidin-3-ylcarbamate. The resultingmaterial was treated with HCl/dioxane for 1 hour, and then concentratedto give the title compound.

Example 117B3-nitro-4-(1-(tetrahydrofuran-3-yl)azetidin-3-ylamino)benzenesulfonamide4-Fluoro-3-nitrobenzenesulfonamide (0.084 g),1-(tetrahydrofuran-3-yl)azetidin-3-amine

(0.090 g) and triethylamine (0.266 ml) in tetrahydrofuran (3 mL) washeated to 60° C. After stirring for 4 hours, the reaction was cooled,the tetrahydrofuran was removed and the residue was partitioned betweendichloromethane (200 mL) and water (20 mL). The organic layer wasseparated, washed with brine (25 mL), dried over magnesium sulfate,filtered, and concentrated to give the title compound.

Example 117C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylazetidin-3-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 117B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz, CDCl₃)δ 10.39-9.79 (m, 1H), 9.17 (s, 1H), 8.87 (d, 1H), 8.51 (d, 1H), 8.15(dd, 2H), 7.94 (d, 1H), 7.68 (d, 1H), 7.48-7.42 (m, 1H), 7.23 (d, 2H),6.91 (d, 2H), 6.69 (d, 1H), 6.54 (dd, 2H), 5.99 (d, 1H), 4.29 (d, 1H),4.01-3.73 (m, 4H), 3.66 (d, 2H), 3.08 (s, 6H), 2.76 (s, 2H), 2.21 (s,6H), 2.03-1.83 (m, 3H), 1.64 (s, 2H), 1.42 (d, 2H), 0.93 (s, 6H).

Example 1184-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 118A (R)-tert-butyl(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methylcarbamate

The title compound was prepared by substituting (S)-tert-butylpyrrolidin-3-ylmethylcarbamate for tert-butyl piperazine-1-carboxylateand dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde inEXAMPLE 1A.

Example 118B(R)-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methanamine

The title compound was prepared by substituting EXAMPLE 118A for EXAMPLE1A in EXAMPLE 1B.

Example 118C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 118B for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.57 (s, 1H), 8.59 (br s, 1H), 8.45 (br s, 1H),8.02 (d, 1H), 7.95 (m, 1H), 7.71 (m, 1H), 7.56 (d, 1H), 7.45 (m, 1H),7.35 (m, 3H), 7.05 (m, 2H), 6.90 (br s, 1H), 6.64 (d, 1H), 6.33 (m, 1H),6.22 (m, 1H), 3.90 (m, 2H), 3.44 (m, 2H), 3.27 (m, 4H), 3.02 (m, 5H),2.73 (m, 3H), 2.59 (m, 2H), 2.19 (m, 6H), 1.95 (m, 2H), 1.85 (m, 2H),1.64 (m, 1H), 1.50 (m, 2H), 1.39 (m, 2H), 1.23 (m, 1H), 0.94 (s, 6H).

Example 1194-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 75F and EXAMPLE 37D in place of EXAMPLE 3J and EXAMPLE 11B,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.69 (s, 1H),8.39 (s, 1H), 8.08 (d, 1H), 8.04 (d, 1H), 7.41-7.59 (m, 4H), 7.35 (d,2H), 7.08 (d, 2H), 6.68 (dd, 1H), 6.37-6.43 (m, 1H), 6.20 (s, 1H), 4.38(d, 2H), 3.73-3.82 (m, 2H), 3.54-3.63 (m, 2H), 3.09 (s, 4H), 2.81 (s,2H), 2.16-2.39 (m, 5H), 1.94 (s, 2H), 1.79-1.93 (m, 4H), 1.40 (t, 2H),0.94 (s, 6H).

Example 1202-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamideExample 120A Trans-4-(aminomethyl)cyclohexanol

Tert-butyl ((1r,4r)-4-hydroxycyclohexyl)methylcarbamate (1 g) indichloromethane (10 mL) was treated with trifluoroacetic acid (5 mL) at0° C. for 10 minutes and at room temperature for 30 minutes. Thereaction mixture was concentrated and dried in vacuo to provide thetitle compound as a trifluoroacetic acid salt.

Example 120B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-hydroxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide

A mixture of EXAMPLE 53A (211 mg), EXAMPLE 120A (104 mg) andN-ethyl-N-isopropylpropan-2-amine (0.3 mL) in dimethylsulfoxide (2 mL)was heated at 150° C. in a Biotage Initiator microwave synthesizer for1.5 hours and concentrated. The residue was purified by reverse phaseHPLC on a C18 column using a gradient of 40-60% acetonitrile in 0.1%trifluoroacetic acid water to give the title compound as atrifluoroacetate salt. The trifluoroacetic acid salt was dissolved indichloromethane (30 mL) and washed with 50% aqueous NaHCO₃. The organiclayer was dried over anhydrous Na₂SO₄, filtered, and concentrated togive the title compound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.69(s, 1H), 11.41 (s, 1H), 8.61 (t, 1H), 8.53-8.58 (m, 1H), 8.04 (d, 1H),7.76-7.83 (m, 1H), 7.47-7.56 (m, 3H), 7.34 (d, 2H), 7.07-7.11 (m, 1H),7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 4.82-4.99 (m,1H), 4.50 (d, 1H), 3.26-3.31 (m, 2H), 3.23 (t, 1H), 3.07 (s, 4H), 2.76(s, 2H), 2.10-2.28 (m, 6H), 2.05 (dd, 1H), 1.95 (s, 2H), 1.84 (t, 2H),1.52-1.76 (m, 2H), 1.41-1.51 (m, 1H), 1.38 (t, 2H), 0.95-1.25 (m, 4H),0.92 (s, 6H)

Example 1212-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamideExample 121A (4-methoxycyclohexyl)methanol

4-Methoxycyclohexanecarboxylic acid (7 g) in tetrahydrofuran (20 mL) wastreated with 1 M (in tetrahydrofuran) borane-tetrahydrofuran complex(100 mL) overnight. The mixture was concentrated and the residue wasdissolved in methanol (100 mL) and concentrated HCl (10 mL). Theresulting mixture was stirred for 1 hour and concentrated. The residuewas dissolved in dichloromethane and washed with water. The organiclayer was dried over Na₂SO₄, filtered, and concentrated to give thetitle compound.

Example 121B 4-((4-methoxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 12A by replacing(1,4-dioxan-2-yl)methanol with EXAMPLE 121A.

Example 121C4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide

Separation of the cis and trans mixture of EXAMPLE 121B on a reversephase HPLC (gradient: 40-55% acetonitrile in 0.1% TFA in water over 25minutes) provided the title compound.

Example 121D2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((cis-4-methoxycyclohexyl)methoxy)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 121C in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.39 (s, 1H), 8.34 (s, 1H),7.96-8.07 (m, 2H), 7.48-7.56 (m, 3H), 7.31-7.42 (m, 3H), 7.04 (d, 2H),6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.02 (d, 2H), 3.39 (s, 1H),3.20 (s, 3H), 3.09 (s, 4H), 2.82 (s, 2H), 2.09-2.34 (m, 6H), 1.96 (s,2H), 1.78-1.86 (m, 3H), 1.54 (dd, 2H), 1.28-1.46 (m, 6H), 0.92 (s, 6H)

Example 122Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 122A Cis-tert-butyl-4-(cyclopropylamino)cyclohexylcarbamate

The title compound was prepared by substituting tert-butyl4-oxocyclohexylcarbamate for 4′-chlorobiphenyl-2-carboxaldehyde andcyclopropylamine for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

Example 122B cis-N¹-cyclopropylcyclohexane-1,4-diaminebis(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 122A for EXAMPLE39A in EXAMPLE 39B.

Example 122CCis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(cyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 122B for EXAMPLE100B in EXAMPLE 100C. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H),9.28 (d, 1H), 8.59 (d, 1H), 8.44 (d, 1H), 8.37 (dd, 1H), 8.12 (d, 1H),7.67 (t, 2H), 7.43 (t, 2H), 7.07 (d, 2H), 6.90 (d, 1H), 6.75 (dd, 1H),6.53 (d, 1H), 6.50 (dd, 1H), 3.56-3.63 (m, 1H), 3.02-3.08 (m, 4H), 2.77(s, 3H), 2.26 (t, 2H), 2.10-2.16 (m, 4H), 2.06 (ddd, 1H), 1.97 (s, 2H),1.74-1.82 (m, 2H), 1.61-1.71 (m, 5H), 1.39 (t, 2H), 0.93 (s, 6H),0.39-0.44 (m, 4H).

Example 123Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 123ATrans-tert-butyl-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexylcarbamate

The title compound was prepared by substitutingtrans-tert-butyl-4-aminocyclohexylcarbamate for tert-butylpiperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 123B trans-N₁-(tetrahydro-2H-pyran-4-yl)cyclohexane-1,4-diaminebis(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 123A for EXAMPLE39A in EXAMPLE 39B.

Example 123CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 123B for EXAMPLE100B in EXAMPLE 100C. ¹H NMR (500 MHz, pyridine-d₅) δ 13.01 (s, 1H),9.28 (d, 1H), 8.48 (d, 1H), 8.38 (dd, 1H), 8.32 (d, 1H), 8.24 (d, 1H),7.67-7.69 (m, 2H), 7.44 (d, 2H), 7.08 (d, 2H), 6.91 (d, 1H), 6.78 (dd,1H), 6.59 (d, 1H), 6.48 (dd, 1H), 4.01 (d, 2H), 3.44-3.49 (m, 1H),3.37-3.43 (m, 2H), 3.01-3.09 (m, 5H), 2.85 (t, 1H), 2.78 (s, 2H), 2.27(t, 2H), 2.13-2.18 (m, 4H), 2.05 (t, 4H), 1.97 (s, 2H), 1.93 (d, 2H),1.52-1.60 (m, 2H), 1.44-1.50 (m, 2H), 1.39 (t, 2H), 1.25-1.34 (m, 2H),0.94 (s, 6H).

Example 124Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 124A Trans-4-morpholinocyclohexanol

Trans-4-Aminocyclohexanol (0.5 g), 1-bromo-2-(2-bromoethoxy)ethane (1.07g) and triethylamine (2.42 mL) were dissolved in anhydrous acetonitrile(20 mL). The reaction mixture was heated at 60° C. overnight. Theorganic solvent was removed under vacuum. The residue was purified withflash column chromatography on silica gel eluting with 7%-10% methanolin dichloromethane to give the title compound.

Example 124BTrans-5-bromo-6-(4-morpholinocyclohexyloxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 124A for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 36A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 124CTrans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 124B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.56 (m, 2H), 8.03 (d, 1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.34 (d,2H), 7.12 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.19 (d,1H), 3.99 (m, 1H), 3.67 (m, 1H), 3.37 (m, 2H), 3.24 (m, 2H), 3.07 (m,4H), 2.89 (m, 1H), 2.71 (m, 2H), 2.16 (m, 6H), 1.96 (s, 3H), 1.80 (m,4H), 1.38 (t, 2H), 1.27 (m, 2H), 0.92 (s, 6H).

Example 125Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 125A4-(((trans)-4-methoxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide

Separation of the cis and trans mixture of EXAMPLE 121B on a reversephase HPLC provided the title compound.

Example 125BTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 125A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 8.34 (s, 1H), 7.96-8.09 (m, 2H),7.51 (dd, 3H), 7.32-7.39 (m, 3H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd,1H), 6.20 (d, 1H), 4.02 (d, 2H), 3.24 (s, 3H), 3.00-3.15 (m, 5H), 2.83(s, 2H), 2.09-2.36 (m, 6H), 2.03 (d, 2H), 1.96 (s, 2H), 1.77-1.86 (m,2H), 1.73 (s, 1H), 1.39 (t, 2H), 1.02-1.17 (m, 4H), 0.92 (s, 6H)

Example 126 tert-butyl4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylateExample 126A tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g) intetrahydrofuran (5 mL) was treated with 1.0 N LiAlH₄ in THE (2.54 mL) at0° C. The reaction mixture was stirred at room temperature for 2 hours.Water (0.6 mL) was added to the reaction mixture drop-wise, followed by2 N aqueous NaOH (0.2 mL). The reaction was stirred for another 1 hour.The solid was removed by filtration via a pack of Celite and washed withethyl acetate. The filtrate was washed with brine, dried over MgSO₄,filtered, and concentrated to give the product.

Example 126B tert-butyl4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 126A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 126C tert-butyl4-{[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenoxy]methyl}-4-fluoropiperidine-1-carboxylateyl)oxy]benzamide

The title compound was prepared by substituting EXAMPLE 126B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.36 (s, 2H), 8.02-8.06 (m, 2H), 7.49-7.53 (m, 3H), 7.40 (d, 1H),7.35 (d, 2H), 7.04 (d, 1H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.21 (d, 1H),4.36 (d, 2H), 3.83-3.85 (m, 2H), 3.09 (s, 4H), 2.33 (s, 2H), 2.27-2.32(m, 4H), 2.13-2.16 (m, 2H), 1.96 (s, 2H), 1.83-1.92 (m, 2H), 1.67-1.75(m, 2H), 1.38-1.41 (m, 11H), 0.92 (s, 6H).

Example 1274-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 126C for EXAMPLE1A in EXAMPLE 1B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.50 (s,1H), 8.14 (d, 1H), 7.90 (d, 2H), 7.80 (dd, 1H), 7.60 (d, 1H), 7.40 (t,1H), 7.35 (d, 2H), 7.25 (t, 1H), 7.13 (d, 1H), 7.05 (d, 2H), 6.61 (dd,1H), 6.30 (dd, 1H), 6.26 (d, 1H), 4.28 (d, 2H), 3.10-3.13 (m, 2H),2.91-3.00 (m, 6H), 2.73 (s, 2H), 1.96-2.02 (m, 4H), 1.77-1.89 (m, 2H),1.39 (t, 2H), 0.93 (s, 6H).

Example 128Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 128A tert-butyl4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate

The title compound was prepared by substituting tert-butylpiperazine-1-carboxylate for morpholine and dihydro-2H-pyran-4(3H)-onefor tert-butyl 4-oxocyclohexylcarbamate in EXAMPLE 39A.

Example 128B 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride

To a solution of EXAMPLE 128A (3.92 g) in ether was added HCl (25 ml, 2Min ether) and the reaction mixture was stirred for 16 hours at roomtemperature. The solid product was filtered off, dried and used in nextstep without further purification.

Example 128CTrans-tert-butyl-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexylcarbamate

The title compound was prepared by substituting EXAMPLE 128B formorpholine in EXAMPLE 39A.

Example 128Dtrans-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexanaminetris(2,2,2-trifluoroacetate)

The title compound was prepared by substituting EXAMPLE 128C for EXAMPLE39A in EXAMPLE 39B.

Example 128ETrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(4-tetrahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 128D for EXAMPLE100B in EXAMPLE 100C. ¹H NMR (500 MHz, pyridine-d₅) δ 13.07 (s, 1H),9.28-9.32 (m, 1H), 8.44 (t, 1H), 8.34-8.39 (m, 2H), 8.10-8.14 (m, 1H),7.66-7.69 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.92 (t, 1H), 6.73-6.77(m, 1H), 6.52-6.55 (m, 1H), 6.49-6.52 (m, 1H), 3.99-4.06 (m, 2H),3.29-3.36 (m, 2H), 3.03-3.09 (m, 4H), 2.77 (s, 2H), 2.62 (s, 8H),2.24-2.29 (m, 3H), 2.10-2.16 (m, 5H), 2.05 (s, 2H), 1.97 (s, 2H), 1.92(s, 2H), 1.70 (d, 2H), 1.57 (td, 2H), 1.34-1.43 (m, 4H), 1.20-1.30 (m,2H), 0.93 (s, 6H).

Example 1294-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 129A (1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol

A suspension of piperidin-4-ylmethanol (0.250 g), sodiumtriacetoxyborohydride (0.690 g) and 1,3-difluoropropan-2-one (0.245 g)were stirred together in dichloromethane. After stirring overnight thereaction was poured into saturated aqueous NaHCO₃ solution (10 mL) andstirred for 15 minutes. The reaction was extracted with dichloromethane(3×25 mL), dried over magnesium sulfate, filtered, and concentrated.Silica gel chromatography (GRACERESOLV 12 g) eluting with a gradient of0.75% to 3% methanol/dichloromethane gave the title compound.

Example 129B4-((1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

To a solution of (1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol(0.068 g) in tetrahydrofuran (1 mL) was added sodium hydride (0.056 g)and the reaction stirred for 30 minutes at room temperature.4-Fluoro-3-nitrobenzenesulfonamide (0.077 g) was added in one portionand stirring was continued for 1 hour. The reaction was poured intowater (20 mL) and extracted with dichloromethane. The pH of the aqueouslayer was adjusted to pH-8 and it was extracted with dichloromethane (50mL). The organic layer was dried over magnesium sulfate, filtered, andconcentrated to give the title compound.

Example 129C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 129B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.47-10.98 (m, 1H), 8.33 (d,1H), 8.03 (d, 2H), 7.50 (dd, 3H), 7.36 (t, 3H), 7.04 (d, 2H), 6.67 (d,1H), 6.39 (dd, 1H), 6.20 (s, 1H), 4.62 (dd, 4H), 4.06 (d, 2H), 3.18-2.71(m, 11H), 2.20 (d, 6H), 1.96 (s, 2H), 1.73 (d, 3H), 1.35 (d, 4H), 0.92(s, 6H).

Example 1304-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 130A (R)-tert-butyl1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substitutingdihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and(R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 130B (R)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine

A solution of EXAMPLE 130A (550 mg) in dichloromethane (25 ml) wascooled in an ice bath under nitrogen. 2,2,2-Trifluoroacetic acid (8.333ml) was added and the reaction was stirred for 2 hours. The product wasobtained by concentration and high vacuum drying.

Example 130C(R)-3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 130B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 130D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a solution of EXAMPLE 3J (90 mg), EXAMPLE 130C (64.2 mg),triethylamine (0.077 ml), N,N-dimethylpyridin-4-amine (38.5 mg) in amixture of dichloromethane (5 ml) and N,N-dimethylformamide (0.5 ml) wasadded N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine,hydrochloric acid (60.4 mg) and the mixture was stirred 18 hours. Thiswas concentrated on high vacuum and the crude was purified by reversephase chromatography with ammonium acetate buffer/acetonitrile. 1H NMR(500 MHz, pyridine-d₅) δ 13.03 (s, 1H), 9.27 (d, 1H), 8.59 (d, 1H), 8.43(d, 1H), 8.37 (dd, 1H), 8.11 (d, 1H), 7.65-7.67 (m, 2H), 7.44 (d, 2H),7.07 (d, 2H), 6.88 (d, 1H), 6.76 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H),4.06 (m, 1H), 3.98 (d, 2H), 3.35 (t, 2H), 3.07 (m, 4H), 2.73-2.80 (m,4H), 2.68-2.72 (m, 1H), 2.36 (q, 1H), 2.11-2.30 (m, 9H), 1.97 (m, 2H),1.62-1.71 (m, 3H), 1.48-1.58 (m, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 1314-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 131A tert-butyl(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substituting2,2-dimethyldihydro-2H-pyran-4(3H)-one for4′-chlorobiphenyl-2-carboxaldehyde and (R)-tert-butylpyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate inEXAMPLE 1A.

Example 131B(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 131A for EXAMPLE130A in EXAMPLE 130B.

Example 131C4-((3R)-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 131B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 131D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 131C for EXAMPLE130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine-d₅) δ 13.03 (d, 1H),9.28 (m, 1H), 8.61 (m, 1H), 8.44 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H),7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.89 (m, 1H), 6.76 (dd,1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.08 (m, 1H), 3.78 (m, 1H), 3.61 (m,1H), 3.07 (m, 4H), 2.71-2.82 (m, 5H), 2.37-2.44 (m, 2H), 2.19-2.29 (m,3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.76 (m, 1H), 1.66 (m, 2H), 1.32-1.49(m, 4H), 1.28 (d, 3H), 1.20 (s, 3H), 0.94 (s, 6H).

Example 1324-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 132A (S)-tert-butyl1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substitutingdihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and(S)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 132B (S)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 132A for EXAMPLE130A in EXAMPLE 130B.

Example 132C(S)-3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 132B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 132D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 132C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.04 (m, 1H),9.27 (d, 1H), 8.58 (d, 1H), 8.43 (d, 1H), 8.37 (dd, 1H), 8.11 (d, 1H),7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.88 (d, 1H), 6.75 (dd,1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.06 (m, 1H), 3.98 (d, 2H), 3.36 (t,2H), 3.07 (m, 4H), 2.68-2.80 (m, 5H), 2.36 (m, 1H), 2.09-2.29 (m, 9H),1.97 (s, 2H), 1.62-1.72 (m, 3H), 1.48-1.60 (m, 2H), 1.39 (t, 2H), 0.94(s, 6H).

Example 1334-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 133A tert-butyl(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substituting2,2-dimethyldihydro-2H-pyran-4(3H)-one for4′-chlorobiphenyl-2-carboxaldehyde and (S)-tert-butylpyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate inEXAMPLE 1A.

Example 133B(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 133A for EXAMPLE130A in EXAMPLE 130B.

Example 133C4-(3S)-(1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 133B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 133D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 133C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.03 (d, 1H),9.28 (m, 1H), 8.61 (m, 1H), 8.43 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H),7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.89 (m, 1H), 6.76 (dd,1H), 6.54 (m, 1H), 6.49 (m, 1H), 4.08 (m, 1H), 3.78 (m, 1H), 3.61 (m,1H), 3.07 (m, 4H), 2.71-2.82 (m, 5H), 2.37-2.44 (m, 2H), 2.19-2.29 (m,3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.76 (m, 1H), 1.66 (m, 2H), 1.33-1.48(m, 4H), 1.28 (d, 3H), 1.20 (s, 3H), 0.94 (s, 6H).

Example 1344-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 134A 4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide

A solution of EXAMPLE 113A (0.8 g) in dichloromethane (10 mL) andtrifluoroacetic acid (10 mL) was stirred at room temperature for 2hours. The solvents were evaporated and the residue triturated withdiethyl ether. The resulting solid was dissolved in 5% aqueous sodiumcarbonate solution (20 mL). The solution was concentrated to dryness andthe resulting solid was triturated with a solution of 10% methanol indichloromethane several times. Evaporation of the organic solvents gavethe title compound.

Example 134B4-((4-methylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 134A (158 mg) in anhydrousN,N-dimethylformamide (4 mL) was added sodium carbonate (64 mg) andmethyl iodide (78 mg). After stirring overnight at room temperature, themixture was evaporated to dryness. The crude product was then absorbedon silica gel (6 g) and purified on a silica gel column eluting with 10%methanol in dichloromethane to give the title compound.

Example 134C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 134B for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.27 (d, 1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H),7.65 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 3.92 (m, 1H), 3.86 (d, 1H), 3.67 (dt, 1H),3.49-3.39 (m, 2H), 3.07 (m, 4H), 2.77 (s, 2H), 3.71 (m, 1H), 2.49 (d,1H), 2.26 (m, 2H), 2.16 (s, 3H), 2.14 (m, 4H), 2.03 (dt, 1H), 1.97 (s,2H), 1.90 (t, 1H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 1354-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 135A4-((4-(2-methoxyethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 2-methoxyethyl bromidefor methyl iodide in EXAMPLE 134B.

Example 135B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-methoxyethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 135A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 12.98 (s, 1H),9.26 (d, 1H), 8.88 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 3.93 (m, 1H), 3.87 (d, 1H), 3.70 (dt, 1H),3.51 (t, 2H), 3.48-3.38 (m, 2H), 3.27 (s, 3H), 3.07 (m, 4H), 2.95 (d,1H), 2.77 (s, 2H), 2.70 (m, 1H), 2.57 (t, 2H), 2.27-2.07 (m, 8H), 1.97(s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 136N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 136A4-((4-acetylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting acetic anhydride formethyl iodide in EXAMPLE 134B.

Example 136BN-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 136A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (s, 1H), 8.85 (s, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.10 (d, 1H),7.65 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (dd, 1H), 6.75 (dd, 1H),6.54 (s, 1H), 6.48 (s, 1H), 4.73 (dd, 1H), 3.93-3.65 (m, 2H), 3.60-3.40(m, 4H), 3.12 (m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.70 (m, 1H), 2.57(t, 2H), 2.14 (s, 3H), 2.27-2.07 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H),0.93 (s, 6H).

Example 1374-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[trans-4-(fluoromethyl)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 137A ethyl 4-fluorobut-2-enoate

Ethyl 2-fluoroacetate (21.0 g) in CH₂Cl₂ (200 mL) at −78° C. was treateddropwise over 45 min with a 1.0 M solution of diisobutylaluminum hydridein CH₂Cl₂ (200 mL) maintaining the internal temperature below −70° C.Stirring was continued at −78° C. for 30 minutes and then(carbethoxymethylene)triphenylphosphorane (70.0 g) was added in oneportion. The reaction mixture was allowed to slowly reach roomtemperature while stirring overnight. It was then quenched withmethanol, filtered and concentrated to give the product as a mixture ofisomers (E/Z=3:1).

Example 137B Trans-ethyl1-benzyl-4-(fluoromethyl)pyrrolidine-3-carboxylate

A mixture of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine(4.5 g) and EXAMPLE 137A (2.5 g) in dichloromethane (50 mL) was cooledto 0° C., treated dropwise with trifluoroacetic acid (0.15 mL), stirredfor 4 hours at 0° C. and neutralized with saturated aqueous Na₂CO₃solution. The mixture was poured into a separatory funnel and the layersseparated. The organic layer was washed with water and brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel with0-20% ethyl acetate in hexanes as eluent to give both the cis and transisomers of the product. Only the trans diastereomers were carried on inthe following steps.

Example 137C Trans-ethyl 4-(fluoromethyl)pyrrolidine-3-carboxylate

EXAMPLE 137B (0.83 g) in ethanol (9 mL) was treated with 10% Pd/C (0.208g) and ammonium formate (1.97 g), refluxed for 1.5 hours, concentrated,dissolved in dichloromethane, filtered through a pad of celite rinsingwith dichloromethane, and concentrated to give the product.

Example 137D Trans-1-benzyl 3-ethyl4-(fluoromethyl)pyrrolidine-1,3-dicarboxylate

EXAMPLE 137C (0.44 g) in dioxane (4 mL) and water (4 mL) at 0° C. wastreated sequentially with Na₂CO₃ (0.89 g) and benzyl chloroformate (0.48mL). The reaction mixture was stirred at 0° C. for 3 hours and was thenallowed to slowly warm to room temperature over 1.5 hours. The reactionmixture was diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), filtered, concentrated and chromatographed on silica gelwith 10-25% ethyl acetate in hexanes as eluent to give the product.

Example 137ETrans-1-(benzyloxycarbonyl)-4-(fluoromethyl)pyrrolidine-3-carboxylicacid

The title compound was prepared by substituting EXAMPLE 137D for EXAMPLE15G in EXAMPLE 15H.

Example 137F Trans-benzyl3-(fluoromethyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate

EXAMPLE 137E (0.563 g) in tetrahydrofuran (10 mL) at 0° C. was treateddropwise with a 1 M solution of borane in tetrahydrofuran (4 mL),stirred for 3 hours and then slowly quenched with saturated aqueousNH₄Cl solution. The reaction mixture was diluted with ethyl acetate,washed with water and brine, dried (MgSO₄), filtered and concentrated togive the product.

Example 137G Trans-benzyl3-(fluoromethyl)-4-((2-nitro-4-sulfamoylphenoxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 137F for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 137HTrans-4-((4-(fluoromethyl)pyrrolidin-3-yl)methoxy)-3-nitrobenzenesulfonamide

EXAMPLE 137G (0.232 g) in acetic acid (2.5 ml) was treated withhydrobromic acid (33 wt % in acetic acid) (0.875 mL) at ambienttemperature, stirred for 1 hour and concentrated. The product wasfree-based using a MEGA BE-SCX column with 1:1 CH₂Cl₂/methanol as eluentfor the hydrobromic acid and acetic acid. The product was released fromthe column with 10% (7 M ammonia in methanol) in CH₂Cl₂ as eluent.

Example 137ITrans-4-((4-(fluoromethyl)-1-(oxetan-3-yl)pyrrolidin-3-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 137H fortert-butyl piperazine-1-carboxylate and 3-oxetanone for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 137J4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[trans-4-(fluoromethyl)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 137I for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.35 (d, 1H), 8.03 (m, 2H), 7.51 (m, 3H), 7.37 (m, 3H), 7.04 (m,2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.21 (d, 1H), 4.45 (m, 6H), 4.21 (d,2H), 3.62 (m, 1H), 3.08 (m, 4H), 2.72 (m, 5H), 2.31 (m, 9H), 1.96 (s,2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1384-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 138A (4-fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate

A mixture of EXAMPLE 37C (1.4 g), methanesulfonyl chloride (1.054 mL),triethylamine (2.99 mL), and 4-dimethylaminopyridine (0.051 g) in CH₂Cl₂(20 mL) was stirred at 0° C. for 2 hours, concentrated andchromatographed on silica gel eluting with 30% ethyl acetate in hexanesto give the product.

Example 138B2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione

A mixture of EXAMPLE 138A (1.8 g) and potassium phthalimide (2.356 g) inN,N-dimethylformamide (30 mL) was heated at 150° C. overnight, dilutedwith ethyl acetate, washed with water and brine, dried (MgSO₄),filtered, concentrated and chromatographed on silica gel eluting with30% ethyl acetate in hexanes to give the product.

Example 138C (4-fluorotetrahydro-2H-pyran-4-yl)methanamine

A mixture of EXAMPLE 138B (1.4 g) and hydrazine (1.548 mL) in ethanol(40 mL) was heated at 70° C. overnight, cooled to room temperature,slurried with CH₂Cl₂ (200 mL) and the solid removed by filtration. Thefiltrate was concentrated and chromatographed on silica gel eluting with100:5:1 ethyl acetate/methanol/NH₄OH to give the product.

Example 138D4-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.44 g), EXAMPLE 138C(0.266 g), and triethylamine (1.11 mL) in tetrahydrofuran (10 mL) washeated at 70° C. overnight, diluted with ethyl acetate, washed withwater and brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel eluting with 50% ethyl acetate in hexanesto give the product.

Example 138E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 138D for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.68 (s,1H), 8.62 (t, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.48-7.54(m, 3H), 7.34 (d, 2H), 7.24 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39(dd, 1H), 6.19 (d, 1H), 3.70-3.77 (m, 4H), 3.50-3.55 (m, 2H), 3.07 (s,4H), 2.76 (s, 2H), 2.14-2.20 (m, 6H), 1.76-1.84 (m, 4H), 1.38 (t, 2H),0.92 (s, 6H).

Example 1394-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 139A tert-butyl4-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)piperidine-1-carboxylate

The title compound was prepared as described in EXAMPLE 53B by replacing1-acetylpiperidin-4-amine with 4-amino-piperidine-1-carboxylic acidtert-butyl ester.

Example 139B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylamino)phenylsulfonyl)benzamide

To a cooled (0° C.) solution of EXAMPLE 139A (960 mg) in dichloromethane(10 mL) was added dropwise trifluoroacetic acid (5 mL). The mixture wasstirred at the temperature for 3 hours. Then, the mixture wasconcentrated under vacuum and the residue was dissolved indichloromethane (200 mL) and washed with aqueous NaHCO₃ and brine. Afterdrying over Na₂SO₄, the mixture was filtered, and evaporation of thesolvent from the filtrate gave the title compound.

Example 139C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a solution of EXAMPLE 139B (120 mg) in tetrahydrofuran (3 mL) andacetic acid (1 mL) was added oxetan-3-one (50.8 mg) andMP-cyanoborohydride (2.15 mmol/g, 150 mg). The mixture was stirred atroom temperature overnight. The mixture was filtered. The filtrate wasconcentrated and the residue was loaded on a silica gel cartridge andeluted with 5-10% 7N NH₃ in methanol in dichloromethane to give thetitle compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.62 (s, 1H),8.51 (d, 1H), 8.20 (d, 1H), 7.99 (d, 1H), 7.74 (m, 1H), 7.48 (m, 3H),7.35 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.36 (dd, 1H), 6.20 (d, 1H),4.54 (t, 2H), 4.43 (t, 2H), 3.66 (m, 1H), 3.44 (m, 3H), 3.04 (m, 5H),2.73 (s, 2H), 2.61 (m, 2H), 2.12 (m, 11H), 1.61 (m, 2H), 1.38 (t, 2H),0.93 (m, 6H).

Example 1404-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclobutylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 139C byreplacing oxetan-3-one with cyclobutanone. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.58 (s, 1H), 8.47 (d, 1H), 8.12 (d, 1H), 7.97(d, 1H), 7.74 (d, 1H), 7.53 (d, 1H), 7.45 (m, 1H), 7.36 (m, 3H), 7.02(m, 3H), 6.64 (dd, 1H), 6.33 (m, 1H), 6.22 (d, 1H), 3.74 (m, 1H), 2.97(m, 6H), 2.73 (s, 3H), 2.15 (m, 15H), 1.67 (m, 4H), 1.38 (t, 2H), 0.93(s, 6H).

Example 1414-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 139C byreplacing oxetan-3-one with 2,2-dimethyltetrahydropyran-4-one. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ 11.60 (s, 1H), 8.50 (d, 1H), 8.15 (m,1H), 7.99 (d, 1H), 7.78 (m, 1H), 7.62 (m, 1H), 7.47 (m, 3H), 7.34 (m,3H), 7.05 (m, 3H), 6.65 (m, 2H), 6.35 (dd, 1H), 6.21 (d, 1H), 4.56 (d,3H), 3.89 (m, 3H), 3.67 (m, 6H), 3.45 (m, 2H), 3.04 (m, 3H), 2.75 (m,3H), 2.14 (m, 3H), 1.71 (m, 5H), 1.16 (s, 9H).

Example 1424-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 142A (S)-tert-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate

(S)-tert-butyl pyrrolidin-3-ylcarbamate (415 mg),(1-ethoxycyclopropoxy)trimethylsilane (1.8 mL) and molecular sieves (500mg) were combined in methanol (4.5 mL). Acetic acid (1.3 mL) was added,followed by sodium cyanoborohydride (420 mg). The resulting mixture washeated to reflux for 4 hours. Insoluble material was filtered off andreaction was made basic to pH 14 with addition of 6M aqueous NaOHsolution. The solution was extracted three times with diethyl ether, andthe combined extracts were dried over MgSO₄, filtered and concentratedto obtain an oil, which was purified by flash chromatography, elutingfirst with 100% dichloromethane, followed by 5% methanol/dichloromethaneand 10% methanol/dichloromethane.

Example 142B (S)-1-cyclopropylpyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 142A for EXAMPLE1A in EXAMPLE 1B.

Example 142C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 142B for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.64 (s, 1H), 8.51 (m, 2H), 8.30 (m, 1H), 8.00(br s, 1H), 7.77 (m, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.97(br s, 1H), 6.67 (dd, 1H), 6.36 (m, 1H), 6.21 (m, 1H), 4.19 (m, 1H),3.00 (m, 5H), 2.74 (m, 3H), 2.64 (m, 1H), 2.36 (m, 1H), 2.15 (m, 6H),1.95 (s, 2H), 1.78 (br s, 1H), 1.68 (m, 1H), 1.38 (t, 2H), 1.23 (m, 1H),0.92 (s, 6H), 0.39 (m, 4H).

Example 1434-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydrofuran-3-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 139C byreplacing oxetan-3-one with 3-oxotetrahydrofuran. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 8.53 (d, 1H), 8.21 (m, 1H), 8.02(m, 1H), 7.80 (dd, 1H), 7.49 (m, 3H), 7.34 (m, 3H), 7.05 (m, 3H), 6.67(dd, 1H), 6.37 (m, 1H), 6.19 (d, 1H), 4.29 (m, 3H), 3.73 (m, 6H), 3.09(m, 4H), 2.76 (m, 2H), 2.05 (m, 8H), 1.68 (m, 2H), 1.37 (m, 2H), 0.94(s, 6H).

Example 1444-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 144A (R)-tert-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate

The title compound was prepared by substituting (R)-tert-butylpyrrolidin-3-ylcarbamate for (S)-tert-butyl pyrrolidin-3-ylcarbamate inEXAMPLE 142A.

Example 144B (R)-1-cyclopropylpyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 144A for EXAMPLE1A in EXAMPLE 1B.

Example 144C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 144B for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 8.53 (d, 2H), 8.32 (d, 1H), 8.02(d, 1H), 7.81 (m, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.03 (m, 3H), 6.67(dd, 1H), 6.37 (m, 1H), 6.20 (d, 1H), 4.21 (m, 1H), 3.00 (m, 5H), 2.74(m, 3H), 2.64 (m, 1H), 2.36 (m, 1H), 2.15 (m, 6H), 1.95 (s, 2H), 1.74(br s, 1H), 1.66 (m, 1H), 1.38 (t, 2H), 1.23 (m, 1H), 0.92 (s, 6H), 0.39(m, 4H).

Example 1454-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 145A (S)-tert-butyl(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methylcarbamate

The title compound was prepared by substituting (R)-tert-butylpyrrolidin-3-ylmethylcarbamate for tert-butyl piperazine-1-carboxylateand dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde inEXAMPLE 1A.

Example 145B(S)-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methanamine

The title compound was prepared by substituting EXAMPLE 145A for EXAMPLE1A in EXAMPLE 1B.

Example 145C(S)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)methylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 145B for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.58 (s, 1H), 8.61 (br s, 1H), 8.46 (s, 1H),7.96 (d, 1H), 7.72 (m, 1H), 7.54 (d, 1H), 7.45 (t, 1H), 7.37 (br s, 2H),7.34 (d, 2H), 7.04 (m, 2H), 6.94 (m, 1H), 6.64 (dd, 1H), 6.34 (m, 1H),6.22 (d, 1H), 3.89 (m, 2H), 3.38 (m, 4H), 3.27 (m, 4H), 3.02 (m, 5H),2.73 (s, 2H), 2.61 (m, 1H), 2.18 (m, 6H), 2.05 (m, 1H), 1.95 (m, 2H),1.85 (m, 2H), 1.64 (m, 1H), 1.50 (m, 2H), 1.38 (m, 2H), 0.94 (s, 6H).

Example 1464-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 120B using3-amino-2,2-dimethylpropan-1-ol in place of EXAMPLE 120A. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 11.35 (s, 1H), 8.96 (t, 1H),8.56 (d, 1H), 8.05 (d, 1H), 7.79 (dd, 1H), 7.46-7.56 (m, 3H), 7.34 (d,2H), 7.10 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d,1H), 5.10 (t, 1H), 3.29 (d, 1H), 3.24 (d, 1H), 3.07 (s, 4H), 2.75 (s,2H), 2.17 (d, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.93 (d, 12H).

Example 1474-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 147A tert-butyl(1-(methylsulfonyl)piperidin-3-yl)methylcarbamate

tert-Butyl piperidin-3-ylmethylcarbamate (500 mg) was dissolved inanhydrous dichloromethane (10 mL), and methanesulfonyl chloride (0.181mL) was added followed by the addition of triethylamine (1.3 mL). Thereaction mixture was stirred at room temperature overnight. The organicsolvent was removed under vacuum. The residue was purified with flashcolumn chromatography on silica gel eluting with 0-70% ethyl acetate inhexane to give the title compound.

Example 147B (1-(methylsulfonyl)piperidin-3-yl)methanamine

EXAMPLE 147A (400 mg) was suspended in 4N HCl in dioxane (10 mL)followed by the addition of anhydrous methanol (1 mL). The clearsolution was stirred at room temperature for 2 hours. The organicsolvent was removed under vacuum. The solid residue was used in the nextstep without further purification.

Example 147C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 53A (50 mg), EXAMPLE 147B (26 mg) and triethylamine (0.088 mL)were dissolved in anhydrous dioxane (1 mL) and N,N-dimethylformamide(0.2 mL). The reaction vial was heated in a Biotage Initiator microwavereactor at 130° C. for 25 minutes. The solvent was removed under vacuum.The residue was purified by reverse phase HPLC on a C18 column using agradient of 20-80% acetonitrile/0.1% trifluoroacetic acid in water togive the title compound as the trifluoroacetate salt. Thetrifluoroacetic acid salt was dissolved in dichloromethane (6 mL) andwashed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄ and concentrated to give the title compound. ¹H NMR(400 MHz, dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 8.56 (m, 2H), 8.03 (d,1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.12 (m, 1H), 7.04 (d,2H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.19 (d, 1H), 3.52 (m, 1H), 3.40 (m,2H), 3.06 (m, 4H), 2.84 (s, 3H), 2.75 (m, 2H), 2.75 (m, 4H), 2.58 (m,1H), 2.16 (m, 6H), 1.95 (s, 3H), 1.76 (m, 2H), 1.52 (m, 1H), 1.37 (m,2H), 0.92 (s, 6H).

Example 148N-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 148A tert-butyl (1-acetylpiperidin-3-yl)methylcarbamate

The title compound was prepared by substituting acetyl chloride formethanesulfonyl chloride in EXAMPLE 147A.

Example 148B 1-(3-(aminomethyl)piperidin-1-yl)ethanone

The title compound was prepared by substituting EXAMPLE 148A for EXAMPLE147A in EXAMPLE 147B.

Example 148CN-[(4-{[(1-acetylpiperidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 148B for EXAMPLE147B in EXAMPLE 147C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.56 (m, 2H), 8.03 (d, 1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.34 (d,2H), 7.12 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.19 (d,1H), 3.99 (m, 1H), 3.67 (m, 1H), 3.37 (m, 2H), 3.24 (m, 2H), 3.07 (m,4H), 2.89 (m, 1H), 2.71 (m, 2H), 2.16 (m, 6H), 1.96 (s, 3H), 1.80 (m,4H), 1.38 (t, 2H), 1.27 (m, 2H), 0.92 (s, 6H).

Example 1494-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 149A (R)-tert-butyl 1-(methylsulfonyl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substituting (R)-tert-butylpyrrolidin-3-ylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate inEXAMPLE 147A.

Example 149B (R)-1-(methylsulfonyl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 149A for EXAMPLE147A in EXAMPLE 147B.

Example 149C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 149B for EXAMPLE147B in EXAMPLE 147C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.65 (s,1H), 8.55 (d, 1H), 8.29 (d, 1H), 8.02 (d, 1H), 7.86 (dd, 1H), 7.49 (m,3H), 7.33 (d, 2H), 7.17 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (dd,1H), 6.20 (d, 1H), 4.41 (m, 1H), 3.69 (m, 1H), 3.39 (m, 3H), 3.06 (m,4H), 2.97 (s, 3H), 2.76 (m, 2H), 2.27 (m, 8H), 1.93 (m, 2H), 1.54 (m,1H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1504-(4-{[2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 150A Ethyl 2-hydroxy-3,3-dimethylcyclohex-1-enecarboxylate

Into a 500 mL round-bottomed flask was added diisopropylamine (3.5 mL)in ether (200 mL). After cooling to −30° C., butyllithium (16 mL) (1.6Min hexane) was added slowly. After stirring 30 minutes, the temperaturewas cooled to −5° C. 2,2-Dimethylcyclohexanone (3 g) was added slowly.The mixture was warmed up to 0° C. and stirred for 1 hour. After coolingto −5° C., hexamethylphosphoramide (8 mL) and ethyl carbonocyanidate(2.5 mL) were added. After stirring at −5° C. for 20 minutes, andwarming to room temperature, the reaction was stirred for 1 hour. Themixture was poured into cold water, and the layers were separated. Theaqueous layer was extracted with ether (3×20 mL). The combined theorganic layers were washed with saturated aqueous NH₄Cl (3×20 mL). Afterdrying over Na₂SO₄, the mixture was filtered and the filtrate wasconcentrated. The crude product was purified by flash chromatography onsilica with 0-10% ethyl acetate in hexanes to provide the titlecompound.

Example 150B Ethyl3,3-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

The title compound was prepared by substituting EXAMPLE 150A for EXAMPLE101A in EXAMPLE 101n.

Example 150C Ethyl2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-enecarboxylate

The title compound was prepared by substituting EXAMPLE 150B for EXAMPLE101B in EXAMPLE 101C.

Example 150D (2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-enyl)methanol

In a 200 mL round-bottomed flask was added EXAMPLE 150C (0.97 g) andlithium borohydride (0.47 g) in ether (20 mL) to give a suspension.Methanol (2.2 mL) was added slowly. The mixture was refluxed overnight.The reaction was then cooled, and methanol was added to quench thereaction. 1N aqueous HCl was then added until the pH<7, and ether (3×30mL) was used to extract the product. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated. The crude material waspurified by flash chromatography on silica with 0-25% ethyl acetate inhexanes to provide the title compound.

Example 150E 2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-enecarbaldehyde

Into a 100 mL round-bottomed flask was added EXAMPLE 150D (0.3 g) andDess-Martin Periodinane (0.6 g) in dichloromethane (10 mL) to give asuspension. The mixture was stirred at room temperature overnight. Afterfiltration, the mixture was washed with saturated aqueous NaHCO₃ (2×20mL), dried over Na₂SO₄, filtered, and concentrated. The crude productwas purified by flash chromatography on silica with 0-25% ethyl acetatein hexanes to provide the title compound.

Example 150F Methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 150E for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 15F for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 150G2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 150F for EXAMPLE101E in EXAMPLE 101F.

Example 150H4-(4-{[2-(4-chlorophenyl)-3,3-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 150G for EXAMPLE3J and EXAMPLE 1F for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (500 MHz,dimethyl sulfoxide-d₆) δ 11.50 (s, 1H), 8.36 (m, 1H), 8.32 (m, 1H), 7.91(d, 1H), 7.59 (m, 2H), 7.40 (t, 1H), 7.35 (d, 2H), 7.25 (m, 1H), 6.94(d, 2H), 6.79 (d, 1H), 6.60 (m, 1H), 6.29 (m, 1H), 6.24 (d, 1H), 3.83(m, 2H), 3.25 (m, 4H), 2.98 (m, 4H), 2.42 (s, 2H), 2.14 (m, 6H), 1.60(m, 6H), 1.25 (m, 3H), 0.86 (s, 6H)

Example 1514-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 151A 1-(1,3-difluoropropan-2-yl)azetidin-3-amine

To a solution of tert-butyl azetidin-3-ylcarbamate (0.256 g) and1,3-difluoropropan-2-one (0.154 g) in dichloromethane (2 mL) was addedsodium triacetoxyborohydride (0.473 g) and the reaction was allowed tostir at room temperature. After 16 hours, the reaction was quenched withsaturated NaHCO₃ solution (10 mL) and extracted into dichloromethane (25mL). The organic layer was dried and concentrated. Silica gelchromatography (GRACERESOLV 12 g) eluting with a gradient of 0.5% to3.5% methanol/dichloromethane followed by treatment with HCl (4.0M indioxane, 3 mL) and methanol (0.5 mL) for 2 hours gave the title compoundafter concentration.

Example 151B4-(1-(1,3-difluoropropan-2-yl)azetidin-3-ylamino)-3-nitrobenzenesulfonamide

To a suspension of 4-chloro-3-nitrobenzenesulfonamide (0.225 g) and1-(1,3-difluoropropan-2-yl)azetidin-3-amine (0.193 g) in dioxane (5 mL)was added diisopropylamine (0.832 mL). The reaction was sonicated andthen heated to 100° C. After stirring overnight, the reaction wasconcentrated and loaded onto silica gel (GRACERESOLV 12 g) and elutedwith a gradient of 0.5% to 3.5% methanol/dichloromethane to give thetitle compound.

Example 151C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 151B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 11.54-11.28 (m, 1H), 8.54 (d,1H), 8.45 (s, 1H), 8.01 (d, 1H), 7.82 (d, 1H), 7.48 (d, 3H), 7.34 (d,2H), 7.04 (d, 2H), 6.90 (d, 1H), 6.67 (d, 1H), 6.37 (s, 1H), 6.20 (s,1H), 4.64-4.23 (m, 6H), 3.81 (s, 2H), 3.08 (s, 4H), 2.75 (s, 3H), 2.15(s, 7H), 1.95 (s, 2H), 1.38 (s, 2H), 0.92 (s, 6H).

Example 1524-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 152A tert-butyl(1-(methylsulfonyl)pyrrolidin-3-yl)methylcarbamate

The title compound was prepared by substituting tert-butylpyrrolidin-3-ylmethylcarbamate for tert-butylpiperidin-3-ylmethylcarbamate in EXAMPLE 147A.

Example 152B (1-(methylsulfonyl)pyrrolidin-3-yl)methanamine

The title compound was prepared by substituting EXAMPLE 152A for EXAMPLE147A in EXAMPLE 147B.

Example 152C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(methylsulfonyl)pyrrolidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 152B for EXAMPLE147B in EXAMPLE 147C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.60 (s,1H), 8.49 (m, 2H), 7.99 (s, 1H), 7.73 (m, 1H), 7.53 (d, 1H), 7.47 (s,1H), 7.42 (m, 1H), 7.34 (d, 2H), 7.04 (m, 3H), 6.65 (m, 1H), 6.35 (s,1H), 6.22 (s, 1H), 3.41 (m, 4H), 3.22 (m, 2H), 3.03 (m, 4H), 2.89 (s,3H), 2.73 (m, 2H), 2.59 (m, 1H), 2.17 (m, 6H), 2.00 (m, 4H), 1.68 (m,1H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 153N-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 153A tert-butyl (1-acetylpyrrolidin-3-yl)methylcarbamate

The title compound was prepared by substituting tert-butylpyrrolidin-3-ylmethylcarbamate for tert-butylpiperidin-3-ylmethylcarbamate and acetyl chloride for methanesulfonylchloride in EXAMPLE 147A.

Example 153B 1-(3-(aminomethyl)pyrrolidin-1-yl)ethanone

The title compound was prepared by substituting EXAMPLE 153A for EXAMPLE147A in EXAMPLE 147B.

Example 153CN-[(4-{[(1-acetylpyrrolidin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 153B for EXAMPLE147B in EXAMPLE 147C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.66 (s,1H), 8.62 (m, 1H), 8.54 (s, 1H), 8.03 (m, 1H), 7.78 (d, 1H), 7.50 (m,3H), 7.35 (t, 2H), 7.09 (s, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.37 (d,1H), 6.20 (s, 1H), 3.56 (m, 1H), 3.42 (m, 4H), 3.43 (m, 4H), 3.23 (m,1H), 3.07 (m, 4H), 2.74 (m, 2H), 2.16 (m, 6H), 1.93 (m, 5H), 1.38 (t,2H), 0.93 (s, 6H).

Example 154N-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 154A (R)-tert-butyl 1-acetylpyrrolidin-3-ylcarbamate

The title compound was prepared by substituting (R)-tert-butylpyrrolidin-3-ylcarbamate for tert-butyl piperidin-3-ylmethylcarbamateand acetyl chloride for methanesulfonyl chloride in EXAMPLE 147A.

Example 154B (R)-1-(3-aminopyrrolidin-1-yl)ethanone

The title compound was prepared by substituting EXAMPLE 154A for EXAMPLE147A in EXAMPLE 147B.

Example 154CN-[(4-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 154B for EXAMPLE147B in EXAMPLE 147. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.61 (s,1H), 8.50 (s, 1H), 8.17 (d, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.49 (m,3H), 7.34 (d, 2H), 7.10 (m, 1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.35 (s,1H), 6.22 (s, 1H), 4.34 (m, 1H), 3.81 (m, 1H), 3.58 (m, 1H), 3.43 (m,1H), 3.05 (m, 4H), 2.74 (s, 2H), 2.19 (m, 9H), 1.96 (m, 5H), 1.38 (t,2H), 0.94 (s, 6H).

Example 1554-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxy-2,2-dimethylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 120B using3-methoxy-2,2-dimethylpropan-1-amine in place of EXAMPLE 120A. ¹H NMR(500 MHz, dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.32 (s, 1H), 8.92 (t,1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.46-7.55 (m, 3H), 7.34(d, 2H), 7.08 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.36-6.42 (m, 1H),6.19 (d, 1H), 3.25-3.30 (m, 5H), 3.19 (s, 2H), 3.07 (s, 4H), 2.76 (s,2H), 2.17 (d, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.96 (s, 6H), 0.92 (s,6H).

Example 1564-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 156A4-(((1R,3R)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting(1R,3R)-3-hydroxycyclopentyl)methylamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 156B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 156A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.05 (s, 1H),9.29 (s, 1H), 8.62 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.10 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.85 (d, 1H), 6.74 (dd, 1H),6.54 (s, 1H), 6.49 (m, 1H), 4.60 (m, 1H), 3.19 (dd, 2H), 3.06 (m, 4H),2.77 (s, 2H), 2.70 (m, 1H), 2.26 (t, 2H), 2.20-2.07 (m, 6H), 2.00 (m,1H), 1.97 (s, 2H), 1.90 (m, 1H), 1.56 (m, 1H), 1.39 (t, 2H), 1.34 (m,1H), 0.93 (s, 6H).

Example 1574-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 157A4-(((1S,3S)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting (1S,3S)-3-hydroxycyclopentyl)methylamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 157B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 157A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.03 (s, 1H),9.29 (s, 1H), 8.60 (t, 1H), 8.44 (d, 1H), 8.32 (dd, 1H), 8.14 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.83 (d, 1H), 6.75 (dd, 1H),6.55 (s, 1H), 6.49 (m, 1H), 4.60 (m, 1H), 3.19 (dd, 2H), 3.06 (m, 4H),2.77 (s, 2H), 2.70 (m, 1H), 2.26 (t, 2H), 2.20-2.07 (m, 6H), 2.00 (m,1H), 1.97 (s, 2H), 1.90 (m, 1H), 1.56 (m, 1H), 1.39 (t, 2H), 1.34 (m,1H), 0.93 (s, 6H).

Example 1584-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 158A4-(((1S,3R)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting (1S,3R)-3-hydroxycyclopentyl)methylamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 158B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1S,3R)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 158A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 12.94 (s, 1H),9.25 (d, 1H), 8.59 (t, 1H), 8.48 (d, 1H), 8.27 (m, 2H), 7.66 (m, 2H),7.45 (d, 2H), 7.08 (d, 2H), 6.77 (dd, 1H), 6.72 (d, 1H), 6.60 (d, 1H),6.47 (m, 1H), 4.53 (m, 1H), 3.30 (m, 2H), 3.06 (m, 4H), 2.78 (s, 2H),2.27 (m, 3H), 2.19-2.10 (m, 5H), 1.98 (m, 3H), 1.85-1.66 (m, 4H), 1.39(t, 2H), 0.94 (s, 6H).

Example 1594-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 159A4-(((1R,3S)-3-hydroxycyclopentyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting (1R,3S)-3-hydroxycyclopentyl)methylamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 159B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(1R,3S)-3-hydroxycyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 158A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.02 (s, 1H),9.28 (d, 1H), 8.59 (t, 1H), 8.44 (d, 1H), 8.29 (d, 1H), 8.13 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.08 (d, 2H), 6.82 (dd, 1H), 6.74 (d, 1H),6.55 (d, 1H), 6.48 (m, 1H), 4.53 (m, 1H), 3.34 (m, 2H), 3.06 (m, 4H),2.77 (s, 2H), 2.27 (m, 3H), 2.19-2.10 (m, 5H), 1.97 (m, 3H), 1.85-1.66(m, 4H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1604-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-2-oxopiperidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting(S)-3-aminopiperidin-2-one for 1-acetylpiperidin-4-amine in EXAMPLE 53B.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.68 (br s, 1H), 8.88 (d, 1H),8.57 (d, 1H), 8.04 (d, 1H), 7.95 (br s, 1H), 7.83 (dd, 1H), 7.55-7.46(m, 3H), 7.35 (d, 2H), 7.16 (d, 1H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.38(m, 1H), 6.21 (d, 1H), 4.41 (m, 1H), 3.22 (m, 2H), 3.09 (br s, 4H), 2.78(br s, 2H), 2.35-2.09 (m, 8H), 1.96 (br s, 2H), 1.86 (m, 2H), 1.39 (t,2H), 0.93 (s, 6H).

Example 1614-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 161A tert-butyl3-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)methyl)azetidine-1-carboxylate

EXAMPLE 82 (305 mg). tert-butyl 3-(aminomethyl)azetidine-1-carboxylate(86 mg) and diisopropyl amine (0.202 mL) in dioxane (3 mL) were heatedto 110° C. After stirring overnight, the reaction was concentrated.Silica gel chromatography (Reveleris, 12 g) eluting with a gradient of0.5% to 3% methanol/dichloromethane (Flow=36 ml/minute) gave the titlecompound.

Example 161B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-(azetidin-3-ylmethylamino)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

To a solution of EXAMPLE 161A (0.257 g) in dichloromethane (5 mL) wasadded trifluoroacetic acid (0.211 mL), After 30 minutes an additional0.2 ml of trifluoroacetic acid was added. After 3 hours, the reactionwas concentrated to give the title compound.

Example 161C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]azetidin-3-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A solution of EXAMPLE 161B (0.118 g), sodium triacetoxyborohydride(0.035 g) and 1,3-difluoropropan-2-one (0.012 g) were stirred togetherin dichloromethane (1 mL) overnight. The reaction was quenched withsaturated aqueous NaHCO₃ solution (10 mL) and extracted intodichloromethane (30 mL). The organic layer was dried and concentrated.Silica gel chromatography (Reveleris 12 g) eluting with a gradient of0.5% to 3.5% methanol/dichloromethane over 30 minutes (Flow=36 ml/min)gave the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.67(s, 1H), 11.47-11.21 (m, 1H), 8.85 (s, 1H), 8.55 (d, 1H), 8.03 (d, 1H),7.80 (dd, 1H), 7.54-7.45 (m, 3H), 7.33 (s, 2H), 7.04 (d, 3H), 6.67 (d,1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.43 (dt, 4H), 3.56 (t, 2H), 3.46 (s,2H), 3.12 (m, 6H), 2.74 (m, 3H), 2.17 (m, 7H), 1.95 (s, 2H), 1.39 (d,2H), 0.92 (s, 6H).

Example 1624-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylazetidin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting oxetan-3-one for1,3-difluoropropan-2-one in EXAMPLE 161C. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 11.51-11.03 (m, 1H), 8.81 (s,1H), 8.54 (d, 1H), 8.02 (d, 1H), 7.79 (dd, 1H), 7.50 (dd, 3H), 7.34 (d,2H), 7.04 (d, 3H), 6.67 (d, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.57 (s,2H), 4.43-4.35 (m, 2H), 3.82 (s, 1H), 3.59 (t, 2H), 3.44 (t, 2H), 3.20(s, 2H), 3.06 (s, 4H), 2.73 (s, 3H), 2.18 (s, 6H), 1.95 (s, 2H), 1.39(d, 2H), 0.92 (s, 6H).

Example 1634-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 163A tert-butyl4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)methyl)piperidine-1-carboxylate

The title compound was prepared by substituting tert-butyl4-(aminomethyl)piperidine-1-carboxylate for 1-acetylpiperidin-4-amine inEXAMPLE 53B.

Example 163B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylmethylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 163A for EXAMPLE1A in EXAMPLE 1B.

Example 163C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(1-oxetan-3-ylpiperidin-4-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 163B for EXAMPLE161B and oxetan-3-one for 1,3-difluoropropan-2-one in EXAMPLE 161C. ¹HNMR (500 MHz, dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 8.60 (t, 1H), 8.54(d, 1H), 8.03 (d, 1H), 7.79 (dd, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.09(d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 4.55(t, 2H), 4.46 (t, 2H), 3.52 (br s, 1H), 3.28 (m, 2H), 3.17 (d, 1H), 3.06(m, 4H), 2.82 (m, 2H), 2.74 (m, 2H), 2.17 (m, 6H), 1.95 (m, 3H), 1.72(m, 3H), 1.38 (t, 2H), 1.28 (m, 2H), 0.92 (s, 6H).

Example 1644-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-cyclopropylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 163B for(S)-tert-butyl pyrrolidin-3-ylcarbamate in EXAMPLE 142A. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 11.96 (br s, 1H), 11.62 (br s, 1H), 8.50(m, 2H), 7.98 (d, 1H), 7.72 (m, 1H), 7.52 (d, 1H), 7.45 (m, 2H), 7.34(d, 2H), 7.04 (m, 2H), 6.94 (m, 1H), 6.64 (dd, 1H), 6.34 (m, 1H), 6.22(d, 1H), 3.28 (m, 3H), 3.04 (m, 5H), 2.72 (s, 2H), 2.64 (m, 1H), 2.64(m, 1H), 2.36 (m, 1H), 2.16 (m, 7H), 1.95 (s, 2H), 1.68 (m, 3H), 1.38(t, 2H), 1.18 (m, 3H), 0.94 (s, 6H), 0.35 (m, 3H).

Example 1654-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 165A4-((4-(2-fluoroethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 2-fluoro-ethyl bromidefor methyl iodide in EXAMPLE 134B.

Example 165B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2-fluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 165A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (d, 1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.92 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (dd, 1H), 3.93 (m, 1H), 4.63, 4.51 (dt, 2H),3.95-3.85 (m, 2H), 3.68 (dt, 1H), 3.43-3.37 (m, 2H), 3.07 (m, 4H), 2.92(d, 1H), 2.77 (s, 2H), 2.65 (m, 2H), 2.59 (m, 1H), 2.26 (m, 2H),2.17-2.08 (m, 5H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1664-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 166A4-((4-(2,2-difluoroethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 2,2-difluoro-ethylbromide for methyl iodide in EXAMPLE 134B.

Example 166B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 166A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.01 (s, 1H),9.26 (d, 1H), 8.86 (t, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.11 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.93 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 6.31, 6.20, 6.09 (tt, 1H), 3.90 (m, 1H),3.85 (d, 1H), 3.67 (dt, 1H), 3.49-3.30 (m, 2H), 3.07 (m, 4H), 2.84 (d,1H), 2.82-2.75 (m, 4H), 2.69 (d, 1H), 2.33 (dt, 1H), 2.27-2.20 (m, 3H),2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1674-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 167A4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 173A fortert-butyl piperazine-1-carboxylate and 3-oxetanone for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 167B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-oxetan-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 167A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.69 (s,1H), 8.39 (s, 1H), 8.09 (d, 1H), 8.04 (d, 1H), 7.52 (m, 4H), 7.35 (d,2H), 7.05 (m, 2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (s, 1H), 4.57 (t,2H), 4.48 (m, 2H), 4.38 (d, 2H), 4.02 (m, 1H), 3.63 (m, 2H), 3.08 (m,4H), 2.74 (m, 4H), 2.17 (m, 6H), 1.88 (m, 6H), 1.40 (t, 2H), 0.93 (s,6H).

Example 1684-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 168A (S)-methyl 4,4-difluoropyrrolidine-2-carboxylate

(S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate(0.472 g) in CH₂Cl₂ (1 mL) was treated with trifluoroacetic acid (1.4mL), stirred at ambient temperature for 4 hours, and concentrated. Theproduct was free-based using a MEGA BE-SCX column with 1:1CH₂Cl₂/methanol as eluent for the trifluoroacetic acid. The product wasreleased from the column with 5% (7 M ammonia in methanol) in CH₂Cl₂ aseluent.

Example 168B (S)-methyl4,4-difluoro-1-(oxetan-3-yl)pyrrolidine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 168A fortert-butyl piperazine-1-carboxylate and 3-oxetanone for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 168C (S)-(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-2-yl)methanol

EXAMPLE 168B (0.180 g) in tetrahydrofuran (3 mL) was treatedsequentially with a solution of calcium chloride (0.245 g) in ethanol (3mL) and NaBH₄ (0.167 g) and then stirred at ambient temperature for 7hours. The reaction was quenched with saturated aqueous NH₄Cl solutionand extracted with ethyl acetate. The combined extracts were washed withbrine, dried (MgSO₄), filtered, concentrated and chromatographed onsilica gel with 50% ethyl acetate in hexanes as eluent to give theproduct.

Example 168D(S)-4-((4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-2-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 168C for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 168E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2S)-4,4-difluoro-1-oxetan-3-ylpyrrolidin-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 168D for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.69 (s,1H), 8.38 (s, 1H), 8.06 (m, 2H), 7.49 (m, 4H), 7.35 (d, 2H), 7.05 (d,2H), 6.68 (dd, 1H), 6.40 (m, 1H), 6.21 (s, 1H), 4.54 (m, 3H), 4.43 (t,1H), 4.23 (m, 1H), 4.12 (m, 2H), 3.44 (m, 2H), 3.12 (m, 7H), 2.58 (m,1H), 2.29 (m, 7H), 1.97 (s, 2H), 1.40 (t, 2H), 0.93 (s, 6H).

Example 1694-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 169A tert-butyl3-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared as described in EXAMPLE 53B by replacing1-acetylpiperidin-4-amine with tert-butyl3-(aminomethyl)morpholine-4-carboxylate.

Example 169B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(morpholin-3-ylmethylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 139B byreplacing EXAMPLE 139A with EXAMPLE 169A.

Example 169C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydro-2H-pyran-4-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 139C byreplacing EXAMPLE 139B and oxetan-3-one with EXAMPLE 169B andtetrahydropyran-4-one, respectively. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 8.77 (m, 1H), 8.57 (d, 1H), 8.05(d, 1H), 7.84 (dd, 1H), 7.52 (m, 3H), 7.34 (m, 2H), 7.03 (m, 3H), 6.68(dd, 1H), 6.40 (dd, 1H), 6.18 (d, 1H), 3.86 (m, 2H), 3.72 (m, 2H), 3.11(m, 6H), 2.74 (m, 4H), 2.20 (m, 6H), 1.95 (m, 3H), 1.51 (m, 7H), 0.92(s, 6H).

Example 1704-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclobutylmorpholin-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 139C byreplacing EXAMPLE 139B and oxetan-3-one with EXAMPLE 169B andcyclobutanone. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.68 (s, 1H),8.72 (s, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.84 (dd, 1H), 7.52 (m, 3H),7.34 (m, 3H), 7.03 (m, 4H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.18 (d, 1H),3.47 (m, 3H), 3.10 (m, 6H), 2.72 (m, 6H), 2.25 (m, 8H), 1.95 (m, 4H),1.56 (m, 3H), 1.38 (m, 2H), 0.92 (s, 6H).

Example 1714-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-tetrahydrofuran-3-ylmorpholin-3-yl)methyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 139C byreplacing EXAMPLE 139B and oxetan-3-one with EXAMPLE 169B and3-oxotetrahydrofuran, respectively. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.64 (s, 1H), 8.66 (s, 1H), 8.53 (d, 1H), 8.01(d, 1H), 7.80 (d, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.98(d, 1H), 6.66 (dd, 1H), 6.37 (d, 1H), 6.19 (d, 1H), 3.68 (m, 8H), 3.05(m, 6H), 2.85 (m, 3H), 2.73 (s, 2H), 2.25 (m, 6H), 1.91 (m, 3H), 1.37(m, 3H), 0.95 (m, 6H).

Example 1724-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 163B fortert-butyl piperazine-1-carboxylate and 1,3-difluoropropan-2-one for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.40 (br s, 1H), 8.57 (m, 2H),8.03 (d, 1H), 7.78 (d, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.07 (d, 1H),7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (m 1H), 6.19 (d, 1H), 4.63 (d, 2H),4.53 (d, 2H), 3.28 (m, 2H), 3.07 (m, 4H), 2.89 (m, 2H), 2.74 (m, 2H),2.40 (m, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.67 (m, 3H), 1.38 (t, 2H),1.23 (m, 3H), 0.94 (s, 6H).

Example 1734-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 173A4-((4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 126B for EXAMPLE1A in EXAMPLE 1B.

Example 173B4-((1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

To EXAMPLE 173A (0.24 g) in methanol (3 mL) was added 3A molecularsieves (0.1 g), followed sequentially by acetic acid (0.31 mL),(1-ethoxycyclopropoxy)trimethylsilane (0.64 mL), and sodiumcyanoborohydride (0.148 g). The reaction was heated under refluxovernight. After cooling, the reaction mixture was loaded onto a silicagel column. After drying, the column was eluted with 100:2:0.2 ethylacetate/methanol/NH₄OH to give the title compound.

Example 173C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 173B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.65 (s,1H), 8.33 (s, 1H), 8.01 (m, 2H), 7.53 (d, 1H), 7.48-7.49 (m, 2H),7.34-7.38 (m, 3H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.38 (dd, 1H), 6.21 (d,1H), 4.32 (d, 2H), 3.70-3.77 (m, 2H), 3.07 (s, 4H), 2.92 (s, 2H), 2.80(s, 2H), 2.58 (s, 2H), 2.25 (s, 4H), 2.13-2.16 (m 2H), 1.38 (t, 2H),0.92 (s, 6H), 0.40-0.49 (m, 4H).

Example 1744-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A suspension of EXAMPLE 53A (120 mg), (4-methoxyphenyl)methanamine (31mg) and Hunig'sBase (0.159 mL) in dimethylsulfoxide (2 mL) was heatedfor 2 hours at 150° C. in a Biotage Initiator microwave reactor. Thereaction mixture was diluted with methanol (2 mL) and purified byreverse phase HPLC (C8, 30%-100% CH₃CN/water/0.1% trifluoroacetic acid).¹H NMR (500 MHz, pyridine-d₅) δ 13.07 (s, 1H), 9.32 (d, 1H), 9.17 (t,1H), 8.43 (d, 1H), 8.28 (dd, 1H), 8.08 (d, 1H), 7.64-7.68 (m, 2H), 7.44(d, 2H), 7.38 (d, 2H), 7.07 (d, 2H), 6.97-7.02 (m, 2H), 6.90 (d, 1H),6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (dd, 1H), 4.55 (d, 2H), 3.68 (s, 3H),3.03-3.09 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.10-2.17 (m, 4H), 1.97(s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1754-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(trifluoromethoxy)benzyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting(3-trifluoromethoxyphenyl)methanamine for (4-methoxyphenyl)methanaminein EXAMPLE 174. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H), 9.38 (t,1H), 9.31 (d, 1H), 8.42 (d, 1H), 8.28 (dd, 1H), 8.08 (d, 1H), 7.65 (ddd,2H), 7.41-7.46 (m, 3H), 7.36-7.40 (m, 2H), 7.07 (d, 2H), 6.88 (d, 1H),6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (d, 1H), 4.73 (d, 2H), 3.02-3.08 (m,4H), 2.77 (s, 2H), 2.22-2.28 (m, 2H), 2.09-2.16 (m, 4H), 1.97 (s, 2H),1.39 (t, 2H), 0.93 (s, 6H).

Example 1764-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-methoxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting(3-methoxyphenyl)methanamine for (4-methoxyphenyl)methanamine in EXAMPLE174. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H), 9.27-9.32 (m, 2H),8.42 (d, 1H), 8.26 (dd, 1H), 8.08 (d, 1H), 7.64-7.67 (m, 2H), 7.44 (d,2H), 7.32 (t, 1H), 7.14 (s, 1H), 7.04-7.09 (m, 3H), 6.88-6.94 (m, 2H),6.74 (dd, 1H), 6.52 (d, 1H), 6.48-6.50 (m, 1H), 4.64 (d, 2H), 3.68 (s,3H), 3.03-3.09 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.10-2.18 (m, 4H),1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1774-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting(4-difluoromethoxyphenyl)methanamine for (4-methoxyphenyl)methanamine inEXAMPLE 174. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H), 9.32 (d,1H), 9.28 (t, 1H), 8.42 (d, 1H), 8.28 (dd, 1H), 8.07 (d, 1H), 7.66 (t,1H), 7.64 (d, 1H), 7.58 (s, 1H), 7.44 (s, 2H), 7.26 (s, 1H), 7.25 (d,1H), 7.07 (d, 2H), 6.87 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (dd,1H), 4.64 (d, 2H), 3.03-3.10 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H),2.11-2.17 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1784-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxaspiro[4.5]dec-8-ylamino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting1,4-dioxa-spiro[4.5]dec-8-ylamine for 1-acetylpiperidin-4-amine inEXAMPLE 53B. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.67 (br s, 1H),8.55 (d, 1H), 8.26 (d, 1H), 8.04 (d, 1H), 7.81 (dd, 1H), 7.54-7.46 (m,3H), 7.35 (d, 2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (m,1H), 6.19 (d, 1H), 3.89 (s, 4H), 3.78 (m, 1H), 3.07 (br s, 4H), 2.78 (brs, 2H), 2.28-2.11 (m, 6H), 2.00-1.88 (m, 4H), 1.75-1.57 (m, 4H),1.54-1.35 (m, 4H), 0.92 (s, 6H).

Example 179Trans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 179A tert-butyl trans-4-acetamidocyclohexylcarbamate

Tert-butyl (trans)-4-aminocyclohexylcarbamate (1.500 g) andtriethylamine (2.93 mL, 2.125 g) were added to dichloromethane andstirred until the tert-butyl (trans)-4-aminocyclohexylcarbamate haddissolved completely. Acetyl chloride (0.577 g) was added slowly, andthe solution was stirred at room temperature for 16 hours. The solventwas removed, and the residue taken up in ethyl acetate, washed with pH 4buffer, washed with brine, dried with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under vacuum.

Example 179B N-(trans-4-aminocyclohexyl)acetamide

The title compound was prepared by substituting EXAMPLE 179A for EXAMPLE1A in EXAMPLE 1B.

Example 179CTrans-N-[(4-{[4-(acetylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 179B for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (br s, 1H), 8.55 (d, 1H), 8.20 (d, 1H),8.04 (d, 1H), 7.82-7.76 (m, 2H), 7.53-7.46 (m, 3H), 7.35 (d, 2H), 7.16(d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 3.57(m, 2H), 3.07 (br s, 4H), 2.75 (br s, 2H), 2.28-2.10 (m, 6H), 2.03-1.94(m, 4H), 1.83 (d, 2H), 1.80 (s, 3H), 1.55-1.24 (m, 6H), 0.92 (s, 6H).

Example 1804-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 180A (R)-tert-butyl1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate

To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg) and1,1-difluoro-2-iodoethane (618 mg) in N,N-dimethylformamide (6 mL) wasadded N-ethyl-N-isopropylpropan-2-amine (1.403 ml) and the mixture wasstirred at 70° C. for 72 hours. The reaction mixture was concentratedand the crude product was purified on silica gel withmethanol/dichloromethane.

Example 180B (R)-1-(2,2-difluoroethyl)pyrrolidin-3-amine

To a solution of EXAMPLE 180A (525 mg) in a mixture of dichloromethane(3 mL) and methanol (4.0 mL) was added hydrogen chloride, 4M in dioxane(5.24 mL) and the reaction was stirred for 1.5 hours. The reaction wasconcentrated and the crude material was taken up in dichloromethane andthe solvent evaporated, then taken up in ether and the solventevaporated, and then dried on high vacuum.

Example 180C(R)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 180B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 180D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 180C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.02 (m, 1H),9.27 (d, 1H), 8.55 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.10 (d, 1H),7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.83 (d, 1H), 6.75 (dd,1H), 6.54 (m, 1H), 6.48 (m, 1H), 6.04-6.29 (m, 1H), 4.06 (m, 1H), 3.07(m, 4H), 2.83-2.95 (m, 4H), 2.74-2.82 (m, 3H), 2.47 (m, 1H), 2.09-2.30(m, 8H), 1.97 (s, 2H), 1.67 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1814-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 181A (S)-tert-butyl 1-(2-fluoroethyl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substituting 1-fluoro-2-iodoethanefor 1,1-difluoro-2-iodoethane and (S)-tert-butylpyrrolidin-3-ylcarbamate for (R)-tert-butyl pyrrolidin-3-ylcarbamate inEXAMPLE 180A.

Example 181B (S)-1-(2-fluoroethyl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 181A for EXAMPLE180A in EXAMPLE 180B.

Example 181C(S)-4-(1-(2-fluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 181B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 181D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 181C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (m, 1H),9.26 (d, 1H), 8.56 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H),7.63-7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.82 (d, 1H), 6.75 (dd,1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.60 (t, 1H), 4.51 (t, 1H), 4.05 (m,1H), 3.07 (m, 4H), 2.84 (m, 1H), 2.66-2.79 (m, 6H), 2.39 (q, 1H),2.20-2.29 (m, 3H), 2.15 (m, 5H), 1.97 (s, 2H), 1.66 (m, 1H), 1.39 (t,2H), 0.94 (s, 6H).

Example 1824-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 182A (S)-tert-butyl1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substituting (S)-tert-butylpyrrolidin-3-ylcarbamate for (R)-tert-butyl pyrrolidin-3-ylcarbamate inEXAMPLE 180A.

Example 182B (S)-1-(2,2-difluoroethyl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 182A for EXAMPLE180A in EXAMPLE 180B.

Example 182C(S)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 182B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 182D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 182C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.02 (m, 1H),9.27 (d, 1H), 8.54 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H),7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.82 (d, 1H), 6.75 (dd,1H), 6.54 (m, 1H), 6.48 (m, 1H), 6.04-6.29 (m, 1H), 4.06 (m, 1H), 3.07(m, 4H), 2.83-2.95 (m, 4H), 2.74-2.82 (m, 3H), 2.47 (m, 1H), 2.09-2.30(m, 8H), 1.97 (s, 2H), 1.67 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1834-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,b]pyridin-5-yloxy)benzamideExample 183A (R)-tert-butyl 1-(2-fluoroethyl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substituting 1-fluoro-2-iodoethanefor 1,1-difluoro-2-iodoethane in EXAMPLE 180A.

Example 183B (R)-1-(2-fluoroethyl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 183A for EXAMPLE180A in EXAMPLE 180B.

Example 183C(R)-4-(1-(2-fluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 183B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 183D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2-fluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 183C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (m, 1H),9.26 (d, 1H), 8.56 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H),7.63-7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.83 (d, 1H), 6.75 (dd,1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.60 (t, 1H), 4.50 (t, 1H), 4.04 (m,1H), 3.07 (m, 4H), 2.84 (m, 1H), 2.66-2.79 (m, 6H), 2.39 (q, 1H),2.19-2.28 (m, 3H), 2.14 (m, 5H), 1.97 (s, 2H), 1.66 (m, 1H), 1.39 (t,2H), 0.94 (s, 6H).

Example 1844-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 184A (S)-tert-butyl3-((2-nitro-4-sulfamoylphenoxy)methyl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.300 g) in tetrahydrofuran(5 mL) was added sodium hydride (0.238 g). After stirring for 15minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.295 g) was added andreaction stirred at room temperature. After 1 hour, the reaction waspartitioned between water (25 mL) and dichloromethane (50 mL) and thereaction quenched with 1N aqueous HCl (5.96 mL). The organic layer wasseparated, dried over magnesium sulfate, filtered, and concentrated.Silica gel chromatography (Reveleris 12 g) eluting with a gradient of0.2% to 2% methanol/dichloromethane over 30 minutes (flow=36 m/minute)gave the title compound.

Example 184B(S)-3-nitro-4-((1-(oxetan-3-yl)pyrrolidin-3-yl)methoxy)benzenesulfonamide

To (S)-tert-butyl3-((2-nitro-4-sulfamoylphenoxy)methyl)pyrrolidine-1-carboxylate (0.433g) was added hydrogen chloride (4.0M in dioxane, 1.0 mL). After stirringfor 1 hour, the reaction was concentrated and partitioned betweendichloromethane (50 mL) and saturated aqueous NaHCO₃ solution (50 mL).The aqueous layer was separated and concentrated. The residue wastriturated with methanol (100 mL), filtered and concentrated and treatedwith sodium cyanoborohydride (0.068 g) and cyclobutanone (0.078 g) andstirred overnight. The reaction was partitioned between dichloromethane(50 mL) and water (25 mL) and saturated aqueous NaHCO₃ (10 mL). Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated to give the title compound.

Example 184C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 184B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.64 (s, 1H), 11.45-11.01 (m, 1H), 8.30 (d,1H), 7.98 (dd, 2H), 7.60-7.43 (m, 3H), 7.33 (t, 3H), 7.04 (d, 2H),6.74-6.59 (m, 1H), 6.37 (dd, 1H), 6.21 (d, 1H), 4.49 (td, 2H), 4.33 (s,1H), 4.13 (dd, 2H), 3.79 (s, 2H), 3.44 (dd, 2H), 3.07 (s, 4H), 2.74 (d,6H), 2.19 (d, 6H), 1.98 (d, 2H), 1.74-1.52 (m, 1H), 1.39 (t, 2H), 0.92(s, 6H).

Example 1854-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting(4-hydroxyphenyl)methanamine for (4-methoxyphenyl)methanamine in EXAMPLE174. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H), 11.67 (bs, 1H), 9.32(d, 1H), 9.14 (s, 1H), 8.44 (d, 1H), 8.28 (dd, 1H), 8.09 (d, 1H),7.65-7.68 (m, 2H), 7.44 (d, 2H), 7.37-7.41 (m, 2H), 7.19 (s, 2H), 7.07(d, 2H), 6.93 (d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.49 (dd, 1H), 4.54(d, 2H), 3.02-3.09 (m, 4H), 2.77 (s, 2H), 2.22-2.29 (m, 2H), 2.10-2.17(m, 4H), 1.97 (d, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 1864-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxybenzyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting(3-hydroxyphenyl)methanamine for (4-methoxyphenyl)methanamine in EXAMPLE174. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H), 11.67 (bs, 1H),9.27-9.32 (m, 2H), 8.43 (d, 1H), 8.20 (dd, 1H), 8.08 (d, 1H), 7.66 (t,2H), 7.44 (d, 2H), 7.33 (t, 1H), 7.25 (s, 1H), 7.13 (dd, 1H), 7.07 (d,2H), 6.98 (d, 1H), 6.88 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (dd,1H), 4.64 (d, 2H), 3.02-3.09 (m, 4H), 2.77 (s, 2H), 2.22-2.28 (m, 2H),2.09-2.16 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1874-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(difluoromethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting(3-difluoromethoxyphenyl)methanamine for (4-methoxyphenyl)methanamine inEXAMPLE 174. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H), 9.34 (t,1H), 9.30 (d, 1H), 8.42 (d, 1H), 8.26 (dd, 1H), 8.08 (d, 1H), 7.66 (ddd,2H), 7.40-7.45 (m, 3H), 7.36 (t, 1H), 7.27-7.30 (m, 2H), 7.19 (d, 1H),7.07 (d, 2H), 6.87 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (dd, 1H),4.69 (d, 2H), 3.02-3.08 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.09-2.16(m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1884-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[cis-3-morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 188A Cis-methyl 3-morpholinocyclopentanecarboxylate

The title compound was prepared by substituting methyl3-oxocyclopentanecarboxylate for 4′-chlorobiphenyl-2-carboxaldehyde andmorpholine for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

Example 188B Cis-3-morpholinocyclopentyl)methanol

The title compound was prepared by substituting EXAMPLE 188A for EXAMPLE101C in EXAMPLE 101D.

Example 188C4-((Cis-3-morpholinocyclopentyl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 188B for(1,4-dioxan-2-yl)methanol in EXAMPLE 12A.

Example 188D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[cis-3-morpholin-4-ylcyclopentyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 188C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.57 (s,1H), 8.17 (m, 1H), 7.94 (m, 1H), 7.82 (m, 1H), 7.56 (d, 1H), 7.44 (t,1H), 7.34 (m, 3H), 7.16 (m, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.33 (m,1H), 6.24 (d, 1H), 4.06 (m, 2H), 3.62 (m, 4H), 3.03 (m, 4H), 2.75 (s,2H), 2.35 (m, 2H), 2.19 (m, 6H), 2.03 (m, 2H), 1.96 (s, 2H), 1.78 (m,2H), 1.51 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H)

Example 189Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 189A Trans-(4-Methanesulfonylamino-cyclohexyl)-carbamic acidtert-butyl ester

The title compound was prepared by substituting methanesulfonyl chloridefor acetyl chloride in EXAMPLE 179A.

Example 189B Trans-N-(4-Aminocyclohexyl)-methanesulfonamide

The title compound was prepared by substituting EXAMPLE 189A for EXAMPLE1A in EXAMPLE 1B.

Example 189CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(methylsulfonyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 189B for1-acetylpiperidin-4-amine in EXAMPLE 53B. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.68 (br s, 1H), 8.55 (d, 1H), 8.18 (d, 1H),8.04 (d, 1H), 7.84 (d, 1H), 7.79 (dd, 1H), 7.56-7.47 (m, 3H), 7.34 (d,2H), 7.16 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.19 (d,1H), 3.56 (m, 1H), 3.17 (m, 1H), 3.07 (br s, 4H), 2.93 (s, 3H), 2.75 (brs, 2H), 2.28-2.10 (m, 6H), 2.05-1.90 (m, 6H), 1.55-1.32 (m, 6H), 0.92(s, 6H).

Example 1904-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 190A4-(1-cyclopropylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

The title compound was prepared as described in EXAMPLE 17A by replacing(tetrahydropyran-4-yl)methylamine with 4-amino-1-cyclopropylpiperidine.

Example 190B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 3J and EXAMPLE 190A,respectively. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.66 (s, 1H),8.13 (d, 1H), 8.02 (d, 1H), 7.91 (m, 1H), 7.48 (m, 3H), 7.34 (d, 2H),7.04 (d, 2H), 6.67 (m, 2H), 6.38 (dd, 1H), 6.19 (d, 1H), 3.64 (m, 1H),3.13 (m, 5H), 2.73 (m, 5H), 2.22 (m, 6H), 1.92 (m, 5H), 1.70 (m, 1H),1.41 (m, 5H), 0.94 (s, 6H), 0.41 (m, 4H).

Example 1914-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 191A 3-nitro-4-(piperidin-4-ylmethoxy)benzenesulfonamide

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(0.300 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.223 g).After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.276g) was added and reaction stirred at room temperature. After 1 hour thereaction was partitioned between water (25 mL) and dichloromethane (50mL) and the reaction quenched with 1N aqueous HCl (5.57 mL). The organiclayer was separated, dried over magnesium sulfate, filtered, andconcentrated. Treatment with HCl (4.0M in dioxane, 2 mL) and methanol (2mL) for 1 hour, followed by concentration, trituration withdichloromethane and filtration gave the title compound.

Example 191B3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)methoxy)benzenesulfonamide

To a suspension of 3-nitro-4-(piperidin-4-ylmethoxy)benzenesulfonamide(0.100 g) and cyclobutanone (0.030 g) in methanol (1 mL) was addedsodium cyanoborohydride (0.027 g). After stirring overnight, thereaction was quenched with saturated NaHCO₃ (5 mL) and extracted intodichloromethane (2×10 mL). The organic layer was dried over magnesiumsulfate, filtered, and concentrated to give the title compound.

Example 191C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 191B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.64 (s, 1H), 11.46-10.46 (m, 1H), 8.29 (s,1H), 8.00 (d, 2H), 7.61-7.41 (m, 3H), 7.35 (d, 3H), 7.04 (d, 2H), 6.66(d, 1H), 6.37 (s, 1H), 6.21 (s, 1H), 4.67-4.40 (m, 4H), 4.08 (d, 2H),3.06 (s, 4H), 2.78 (s, 4H), 2.19 (m, 6H), 1.96 (s, 4H), 1.79 (m, 4H),1.39 (s, 4H), 0.93 (s, 6H).

Example 1924-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 192A4-((4-fluoro-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

A mixture of EXAMPLE 173A (0.4 g), dihydro-2H-pyran-4(3H)-one (0.179 g),sodium cyanoborohydride (0.112 g), and acetic acid (0.5 mL) intetrahydrofuran (3 mL) was stirred overnight. The solvents were removedunder reduced pressure. The residue was purified with flash columnchromatography on silica gel eluting with 100:5:0.5 ethylacetate/methanol/NH₄OH to give the desired product.

Example 192B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 192A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.58 (s,1H), 8.25 (s, 1H), 7.96 (d, 1H), 7.93 (d, 1H), 7.57 (d, 1H), 7.45 (t,1H), 7.34-7.37 (m, 3H), 7.26 (d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.34(dd, 1H), 6.23 (d, 1H), 4.34 (d, 2H), 3.93 (dd, 2H), 3.03 (s, 6H), 2.76(s, 4H), 2.09-2.22 (m, 6H), 1.96 (s, 2H), 1.52-1.27 (m, 2H), 1.39 (t,2H), 0.93 (s, 6H).

Example 1934-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 193A4-((4-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting dihydrofuran-3(2H)-onefor dihydro-2H-pyran-4(3H)-one in EXAMPLE 192A.

Example 193B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-tetrahydrofuran-3-ylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 193A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.63 (s,1H), 8.31 (s, 1H), 7.99-8.00 (m, 2H), 7.54 (d, 1H), 7.46-7.48 (m, 2H),7.34-7.35 (m, 3H), 7.05 (d2H), 6.66 (dd, 1H), 6.37 (dd, 1H), 6.21 (d,1H), 4.34 (d, 2H), 3.76-3.83 (m, 3H), 3.62-3.65 (m, 2H), 3.03 (s, 4H),2.79 (s, 4H), 2.24 (s, 2H), 2.15 (s, 2H), 1.84-1.99 (m, 8H), 1.52-1.27(m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1944-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-fluoro-1-(methylsulfonyl)piperidin-4-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 194A4-((4-fluoro-1-(methylsulfonyl)piperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

A mixture of EXAMPLE 173A (0.4 g), methanesulfonyl chloride (0.113 g),and triethylamine (0.64 mL) in dichloromethane (5 mL) was stirredovernight. The reaction mixture was loaded onto a silica gel column andeluted with 100:1 ethyl acetate:methanol to give the clean product.

Example 194B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-fluoro-1-(methylsulfonyl)piperidin-4-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 194A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.66 (s,1H), 8.37 (s, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.49-7.53 (m, 3H), 7.42(d, 1H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.38-6.39 (m, 1H),6.21 (d, 1H), 4.40 (d, 2H), 3.51-3.54 (m, 2H), 3.09 (s, 4H), 2.96-3.01(m, 4H), 2.92 (s, 3H), 2.82 (s, 2H), 2.25-2.34 (m, 4H), 2.13-2.16 (m,6H), 2.01-2.07 (m, 2H0, 1.99 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 1954-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3R)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 195A (R)-tert-butyl3-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)methyl)pyrrolidine-1-carboxylate

The title compound was prepared by substituting (R)-tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate for 1-acetylpiperidin-4-aminein EXAMPLE 53B.

Example 195B(S)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(pyrrolidin-3-ylmethylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 195A for EXAMPLE1A in EXAMPLE 1B.

Example 195C(R)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((1-(oxetan-3-yl)pyrrolidin-3-yl)methylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 195B fortert-butyl piperazine-1-carboxylate and oxetan-3-one for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) 11.67 (s, 1H), 8.81 (t, 1H), 8.55 (d, 1H), 8.02(d, 1H), 7.79 (dd, 1H), 7.50 (m, 3H), 7.35 (m, 2H), 7.04 (m, 3H), 6.67(dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 4.57 (m, 2H), 4.48 (m, 2H), 3.68(m, 2H), 3.30 (m, 2H), 3.06 (m, 4H), 2.74 (m, 3H), 2.56 (m, 3H), 2.44(m, 1H), 2.18 (m, 5H), 1.95 (m, 3H), 1.58 (m, 1H), 1.36 (m, 2H), 0.94(s, 6H).

Example 196Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 196ATrans-4-(4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 12A by replacing(1,4-dioxan-2-yl)methanol withtrans-(4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol (made accordingto the procedures in WO 2008/124878).

Example 196BTrans-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-(((1r,4r)-4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

The title compound was prepared as described in EXAMPLE 1G using EXAMPLE196A in place of EXAMPLE 1F and EXAMPLE 3J in place of EXAMPLE 1E.

Example 196CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 196B (150 mg) in dichloromethane (5 mL) and methanol (2 mL) wastreated with 10% aqueous HCl (3 mL) for 1 hour and concentrated. Theresidue was purified by reverse phase HPLC on a C18 column using agradient of 40-60% acetonitrile in 0.1% trifluoroacetic acid water togive the title compound as a trifluoroacetate salt. The trifluoroaceticacid salt was dissolved in dichloromethane (30 mL) and washed with 50%aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated to give the title compound. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.27 (s, 1H), 8.34 (d, 1H),7.95-8.08 (m, 2H), 7.47-7.55 (m, 3H), 7.32-7.40 (m, 3H), 7.01-7.07 (m,2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 4.54 (d, 1H), 3.96-4.06(m, 2H), 3.10 (s, 4H), 2.84 (s, 2H), 2.05-2.39 (m, 6H), 1.96 (s, 2H),1.46-1.93 (m, 5H), 1.39 (t, 2H), 0.98-1.29 (m, 4H), 0.92 (s, 6H)

Example 1974-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[3-(dimethylamino)propoxy]benzyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 197A 3-(4-(aminomethyl)phenoxy)-N,N-dimethylpropan-1-amine

4-(3-(Dimethylamino)propoxy)benzonitrile (300 mg) in methanol (20 mL)was treated with Raney nickel (wet, 1.5 g) under H₂ (30 psi) for 4 hour.The insoluble material was filtered off and the filtrate wasconcentrated to provide the title compound.

Example 197B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[3-(dimethylamino)propoxy]benzyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 120B usingEXAMPLE 197A in place of EXAMPLE 120A. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.56 (s, 1H), 8.80 (t, 1H), 8.42 (d, 1H), 7.93(d, 1H), 7.52-7.61 (m, 2H), 7.41-7.47 (m, 1H), 7.26-7.36 (m, 5H),7.03-7.08 (m, 2H), 6.89 (d, 2H), 6.73 (d, 1H), 6.61 (dd, 1H), 6.31 (dd,1H), 6.22 (d, 1H), 4.52 (d, 2H), 3.99 (t, 2H), 2.90-3.05 (m, 7H), 2.72(s, 2H), 2.61 (s, 6H), 2.09-2.24 (m, 6H), 1.89-2.04 (m, 5H), 1.38 (t,2H), 0.92 (s, 6H)

Example 1984-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 198A (4-(2-morpholinoethoxy)phenyl)methanamine

The title compound was prepared as described in EXAMPLE 197A using4-(2-morpholinoethoxy)benzonitrile in place of4-(3-(dimethylamino)propoxy)benzonitrile.

Example 198B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-morpholin-4-ylethoxy)benzyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 120B usingEXAMPLE 198A in place of EXAMPLE 120A. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 9.00 (t, 1H), 8.56 (d, 1H), 8.02(d, 1H), 7.72 (dd, 1H), 7.46-7.54 (m, 3H), 7.27-7.36 (m, 4H), 7.01-7.07(m, 2H), 6.89-6.95 (m, 3H), 6.66 (dd, 1H), 6.38 (dd, 1H), 6.18 (d, 1H),4.56 (d, 2H), 4.07 (t, 2H), 3.54-3.61 (m, 4H), 3.06 (s, 4H), 2.71-2.78(m, 4H), 2.07-2.24 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1994-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(E)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 199A4-[((E)-4-Hydroxy-adamantan-1-ylmethyl)-amino]-3-nitro-benzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (0.5 g) and5-(aminomethyl)adamantan-2-ol (0.6 g) in tetrahydrofuran (10 mL) weretreated with triethylamine (1 mL) overnight. The reaction mixture wasconcentrated and the residue was purified by reverse phase HPLC, eluting40-60% acetonitrile in 0.1 trifluoroacetic acid water to give twoisomers, which were temporarily assigned as EXAMPLE 199A and EXAMPLE199B, respectively.

Example 199B4-[((Z)-4-Hydroxy-adamantan-1-ylmethyl)-amino]-3-nitro-benzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (0.5 g) and5-(aminomethyl)adamantan-2-ol (0.6 g) in tetrahydrofuran (10 mL) weretreated with triethylamine (1 mL) overnight. The reaction mixture wasconcentrated and the residue was purified by reverse phase HPLC, eluting40-60% acetonitrile in 0.1 trifluoroacetic acid water to give twoisomers, which were temporarily assigned as EXAMPLE 199A and EXAMPLE199B, respectively.

Example 199C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(E)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 199A in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 11.40 (s, 1H), 8.55 (d, 1H), 8.50(t, 1H), 8.03 (d, 1H), 7.77 (dd, 1H), 7.46-7.54 (m, 3H), 7.31-7.38 (m,2H), 7.14 (d, 1H), 7.01-7.06 (m, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H), 6.19(d, 1H), 4.61 (d, 1H), 3.63 (d, 1H), 3.02-3.16 (m, 6H), 2.75 (s, 2H),2.17 (d, 6H), 2.04 (d, 2H), 1.95 (s, 2H), 1.76-1.88 (m, 3H), 1.49-1.61(m, 6H), 1.38 (t, 2H), 1.29 (d, 2H), 0.92 (s, 6H).

Example 2004-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(Z)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 199B in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 11.39 (s, 1H), 8.55 (d, 1H), 8.51(t, 1H), 8.04 (d, 1H), 7.77 (dd, 1H), 7.46-7.55 (m, 3H), 7.31-7.37 (m,2H), 7.14 (d, 1H), 7.01-7.06 (m, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19(d, 1H), 4.61 (d, 1H), 3.61 (d, 1H), 3.08 (d, 6H), 2.75 (s, 2H), 2.17(d, 6H), 1.79-1.99 (m, 7H), 1.55-1.69 (m, 4H), 1.49 (s, 2H), 1.38 (t,2H), 1.22 (d, 2H), 0.92 (s, 6H).

Example 201N-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 201A4-((1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 12A by replacing(1,4-dioxan-2-yl)methanol with(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethanol.

Example 201BN-({4-[(1S,4S)-bicyclo[2.2.1]hept-5-en-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 201A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 8.35 (d, 1H), 7.95-8.10 (m, 2H),7.47-7.58 (m, 3H), 7.30-7.45 (m, 3H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.40(d, 1H), 5.92-6.23 (m, 3H), 3.65-4.39 (m, 3H), 3.00-3.22 (m, 4H),2.76-2.98 (m, 4H), 2.28 (s, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.71-1.91(m, 1H), 1.33-1.47 (m, 3H), 1.20-1.32 (m, 2H), 0.92 (s, 6H), 0.50-0.66(m, 1H).

Example 2024-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 82 (140 mg) was dissolved in dioxane (3.0 mL), and4-amino-1-methylpyrrolidin-2-one hydrochloride (30 mg) and triethylamine(0.100 mL) were added. The reaction mixture was heated at 110° C. for 40hours. The reaction was concentrated and the crude material was purifiedby preparative HPLC using a C18 column, 250×50 mm, 10μ, and eluting witha gradient of 20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water,giving the product as a trifluoroacetate salt. The salt was dissolved indichloromethane (6 mL) and washed with 50% aqueous NaHCO₃. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated to give the titlecompound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 8.74(d, 1H), 8.37 (br d, 1H), 8.02 (d, 1H), 7.83 (dd, 1H), 7.49 (m, 3H),7.34 (d, 2H), 7.07 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.38 (m, 1H),6.21 (d, 1H), 4.46 (m, 1H), 3.81 (dd, 1H), 3.38 (dd, 1H), 3.08 (br m,4H), 2.82 (dd, 1H), 2.75 (s, 5H), 2.43 (dd, 1H), 2.21 (br m, 4H), 2.16(br t, 2H), 1.95 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2034-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 203A4-(((1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]heptan-2-yl)methoxy)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 201A (340 mg) in tetrahydrofuran (10 mL) andwater (1 mL) was added N-methylmorpholine N-oxide (184 mg) and OsO₄(2.5% in 2-methyl-2-propanol) (1.05 mL). The reaction mixture wasstirred overnight and purified by reverse phase HPLC to provide twoisomers, which were temporarily assigned as EXAMPLE 203A and EXAMPLE203B, respectively.

Example 203B4-(((1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]heptan-2-yl)methoxy)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 201A (340 mg) in tetrahydrofuran (10 mL) andwater (1 mL) was added N-methylmorpholine N-oxide (184 mg) and OsO₄(2.5% in 2-methyl-2-propanol) (1.05 mL). The reaction mixture wasstirred overnight and purified by reverse phase HPLC to provide twoisomers, which were temporarily assigned as EXAMPLE 203A and EXAMPLE203B, respectively.

Example 203C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5R,6S)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 203A in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 8.33 (s, 1H), 7.97-8.07 (m, 2H),7.48-7.55 (m, 3H), 7.41 (d, 1H), 7.32-7.37 (m, 2H), 7.02-7.07 (m, 2H),6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.58 (dd, 2H), 4.07-4.19 (m,2H), 3.82 (t, 1H), 3.51 (t, 1H), 3.09 (s, 4H), 2.81 (s, 2H), 2.09-2.34(m, 8H), 2.04-2.09 (m, 2H), 1.93-2.01 (m, 3H), 1.62-1.77 (m, 2H), 1.39(t, 2H), 1.11 (d, 1H), 0.92 (s, 6H), 0.67-0.76 (m, 1H).

Example 2044-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R,4R,5S,6R)-5,6-dihydroxybicyclo[2.2.1]hept-2-yl]methoxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 203B in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 8.33 (s, 1H), 7.98-8.07 (m, 2H),7.49-7.54 (m, 3H), 7.41 (d, 1H), 7.32-7.36 (m, 2H), 7.02-7.07 (m, 2H),6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.58 (dd, 2H), 4.13 (dd,2H), 3.82 (t, 1H), 3.51 (t, 1H), 3.09 (s, 4H), 2.81 (s, 2H), 2.09-2.35(m, 8H), 2.07 (s, 2H), 1.93-2.02 (m, 3H), 1.61-1.80 (m, 2H), 1.39 (t,2H), 1.11 (d, 1H), 0.92 (s, 6H), 0.66-0.78 (m, 1H).

Example 2054-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 205A Methyl 1,4-dioxaspiro[4.5]decane-7-carboxylate

To a solution of trimethylsilyltrifluoromethanesulfonate (0.034 mL) indry dichloromethane (5 mL) was added 1,2-bis(trimethylsiloxy)ethane(4.55 mL) followed by methyl 3-oxocyclohexanecarboxylate (2.9 g). Thereaction mixture was stirred for 3 hours at −78° C. The reaction mixturewas quenched with dry pyridine (0.5 mL), poured into saturated aqueousNaHCO₃, and extracted with ether. The ether layer was dried overNa₂CO₃/Na₂SO₄. The reaction mixture was concentrated and purified byflash chromatography on silica with 5 to 30% ethyl acetate in hexanes toprovide the title compound.

Example 205B 1,4-dioxaspiro[4.5]decan-7-ylmethanol

The title compound was prepared by substituting EXAMPLE 205A for EXAMPLE101C in EXAMPLE 101D.

Example 205C 3-nitro-4-((3-oxocyclohexyl)methoxy)benzenesulfonamide

Into a 250 mL round-bottomed flask was added sodium hydride (0.5 g) intetrahydrofuran (10 mL) and then 1,4-dioxaspiro[4.5]decan-7-ylmethanol(0.5 g) was added. After the mixture stirred at room temperature for 20minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.65 g) was added. Themixture was stirred at room temperature for overnight. Water (20 mL) wasadded slowly. The aqueous layer was extracted by dichloromethane (3×20mL). The combined organic layers were dried over Na₂SO₄. Afterfiltration, and concentration of the filtrate, the residue was purifiedby reverse phase chromatography, eluting with 30-60% acetonitrile inwater with 0.1% trifluoroacetic acid.

Example 205D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-oxocyclohexyl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 205C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.59 (s,1H), 8.22 (s, 1H), 7.96 (d, 1H), 7.87 (m, 1H), 7.55 (d, 1H), 7.45 (t,1H), 7.35 (m, 3H), 7.20 (m, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.34 (m,1H), 6.23 (d, 1H), 4.07 (d, 2H), 3.04 (m, 4H), 2.76 (s, 2H), 2.35 (m,2H), 2.20 (m, 8H), 1.96 (m, 4H), 1.58 (m, 2H), 1.39 (t, 2H), 0.93 (s,6H).

Example 2064-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dien-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 206A 2-chloro-5,5-dimethylcyclohexa-1,3-dienecarbaldehyde

In a 250 mL round-bottomed flask was added N,N-dimethylformamide (3.5mL) in dichloromethane (30 mL), and the mixture was cooled to −10° C.Phosphoryl trichloride (4 mL) was added dropwise, and the solution waswarmed up to room temperature. 4,4-Dimethylcyclohex-2-enone (5.5 mL) wasthen added slowly, and the mixture was heated to reflux overnight. Thereaction mixture was cooled and quenched with a 0° C. solution of sodiumacetate (25 g in 50 mL water). The aqueous layer was extracted withdiethyl ether (200 mL×3). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated to give the product.

Example 206B2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dienecarbaldehyde

Into a 1 L round-bottomed flask was added EXAMPLE 206A (6.8 g),4-chlorophenylboronic acid (6.5 g), and palladium (II) acetate (0.2 g)in water (100 mL) to give a suspension. Potassium carbonate (15 g) andtetrabutylammonium bromide (10 g) were added. After degassing, themixture was stirred at 45° C. for 4 hours. After cooling and filteringthrough silica gel in a funnel, diethyl ether (4×200 mL) was used toextract the product. The combined organic layers were dried over Na₂SO₄,and filtered. The filtrate was concentrated and purified by flashchromatography on silica with 0-10% ethyl acetate in hexanes to providethe title compound.

Example 206C Methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dienyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 206B for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 15F for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 206D2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dienyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 206C for EXAMPLE101E in EXAMPLE 101F.

Example 206E4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-1,3-dien-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 206D for EXAMPLE3J and EXAMPLE 1F for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.61 (s, 1H), 8.49 (m, 2H), 7.99 (m, 1H), 7.72(m, 1H), 7.53 (d, 1H), 7.41 (m, 4H), 7.12 (d, 2H), 6.99 (m, 1H), 6.66(dd, 1H), 6.35 (m, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.58 (d, 1H), 3.84(m, 2H), 3.26 (m, 4H), 3.06 (m, 4H), 2.88 (s, 2H), 2.24 (m, 6H), 1.61(m, 2H), 1.26 (m, 3H), 1.00 (s, 6H).

Example 2074-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 207A (R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine

The title compound was prepared by substituting (R)-tert-butylpyrrolidin-3-ylcarbamate for tert-butyl azetidin-3-ylcarbamate inEXAMPLE 151A.

Example 207B(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 207A for EXAMPLE151A in EXAMPLE 151B.

Example 207C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 207B for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.52-11.24 (m, 1H), 8.55 (d,1H), 8.37 (d, 1H), 8.03 (d, 1H), 7.83 (dd, 1H), 7.57-7.45 (m, 3H), 7.34(d, 2H), 7.06 (t, 3H), 6.67 (d, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.70(d, 2H), 4.54 (d, 2H), 4.23 (s, 1H), 3.11-2.87 (m, 7H), 2.74 (dd, 4H),2.35-2.13 (m, 7H), 1.95 (s, 2H), 1.70 (s, 1H), 1.39 (d, 2H), 0.92 (s,6H).

Example 2084-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 208A2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-5-iodo-3-(trifluoromethyl)pyridine

A mixture of EXAMPLE 37C (0.537 g),5-iodo-3-(trifluoromethyl)pyridin-2-ol (1.156 g), and triphenylphosphine(1.574 g) in tetrahydrofuran (20 mL) was cooled to 0° C. To thissolution was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.921g). The reaction mixture was stirred overnight. The solvent was removed,and the residue was purified with column flash chromatography on silicagel eluting with 4:1 hexanes/ethyl acetate to give the desired product.

Example 208B6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

EXAMPLE 207A (1.3 g) in tetrahydrofuran (10 mL) was cooled to −42° C.with a cold bath of CH₃CN/dry ice. To this solution was added 2.0 Misopropylmagnesium chloride (1.6 mL) dropwise over 5 minutes. Thereaction mixture was stirred for 30 minutes at −42° C., then allowed towarm to 0° C. over 10 minutes. The reaction mixture was cooled again to−42° C., and SO₂ was bubbled through it for 10 minutes. The reactionmixture was stirred for another 30 minutes. To this solution wassulfuryl dichloride (0.433 g). On warming to room temperature,concentrated NH₄OH (10 mL) was added and the reaction mixture wasstirred for another 2 hours. The reaction mixture was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate three times. The combined organic layers werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by flash column chromatography on silica geleluting with 3:1 hexanes/ethyl acetate to give the title compound.

Example 208C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 208B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.61 (s,1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.98 (d, 1H), 7.55 (d, 1H), 7.42-7.47(m, 2H), 7.36 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.35 (s, 1H), 6.23(s, 1H), 4.56 (d, 2H), 3.75-3.79 (m, 2H), 3.56-3.61 (m, 2H), 3.09 (s,4H), 2.32-2.37 (m, 2H), 2.16 (s, 2H), 1.97-1.99 (m, 2H), 1.79-1.86 (m,4H), 1.40 (t, 2H), 0.93 (s, 6H).

Example 2094-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 209A (S)-tert-butyl(1-(oxetan-3-yl)pyrrolidin-3-yl)methylcarbamate

The title compound was prepared by substituting (R)-tert-butylpyrrolidin-3-ylmethylcarbamate for tert-butyl piperazine-1-carboxylateand 3-oxetanone for 4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 209B (S)-(1-(oxetan-3-yl)pyrrolidin-3-yl)methanamine

The title compound was prepared by substituting EXAMPLE 209A for(S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate inEXAMPLE 168A.

Example 209C(S)-3-nitro-4-((1-(oxetan-3-yl)pyrrolidin-3-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting4-fluoro-3-nitrobenzenesulfonamide for4-chloro-3-nitrobenzenesulfonamide and EXAMPLE 209B for4-methylpiperazin-1-amine dihydrochloride in EXAMPLE 6A.

Example 209D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 209C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.05 (s, 1H), 9.30(d, 1H), 9.02 (t, 1H), 8.42 (d, 1H), 8.34 (dd, 1H), 8.10 (d, 1H), 7.67(dd, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.82 (d, 1H), 6.75 (m, 1H), 6.52(m, 2H), 4.82 (t, 1H), 4.75 (t, 1H), 4.67 (t, 2H), 3.57 (m, 1H), 3.24(t, 2H), 3.07 (m, 4H), 2.75 (m, 3H), 2.57 (dd, 1H), 2.45 (s, 1H), 2.36(t, 1H), 2.26 (s, 2H), 2.18 (m, 5H), 1.93 (m, 3H), 1.56 (m, 1H), 1.39(t, 2H), 0.93 (s, 6H).

Example 210Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 210A (4-methoxycyclohexyl)methanol

The title compound was prepared by substituting4-methoxycyclohexanecarboxylic acid for 1-tert-butyl 4-ethyl4-fluoropiperidine-1,4-dicarboxylate in EXAMPLE 126A.

Example 210BTrans-5-chloro-6-((4-methoxycyclohexyl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 210A fortetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 210CTrans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 210C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.50 (s, 1H), 8.17 (s, 1H), 8.02 (d, 1H), 7.49-7.54 (m, 3H), 7.35(d, 2H), 7.05 (d, 2H), 6.67 (dd, J 1H), 6.39 (s, 1H), 6.21 (s, 1H), 4.20(d, 2H), 3.23 (s, 3H), 3.06-3.09 (m, 4H), 2.15-2.37 (m, 4H), 1.96-2.03(m, 4H), 1.74-1.84 (m, 2H), 1.40 (t, 2H), 1.04-1.13 (m, 4H), 0.93 (s,6H).

Example 211Cis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 211ACis-5-chloro-6-((4-methoxycyclohexyl)methoxy)pyridine-3-sulfonamide

The title compound was isolated as a by-product in the synthesis ofEXAMPLE 210B.

Example 211BCis-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 211A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H), 7.49-7.54 (m, 3H), 7.35(d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.39 (s, 1H), 6.21 (s, 1H), 4.21(d, 2H), 3.20 (s, 3H), 3.06 (s, 4H), 2.15-2.37 (m, 4H), 1.96 (s, 2H),1.80-1.84 (m, 2H), 1.50-1.54 (m, 2H), 1.34-1.44 (m, 6H), 0.93 (s, 6H).

Example 2124-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 212A (S)-tert-butyl 1-(oxetan-3-yl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substituting (S)-tert-butylpyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate and3-oxetanone for 4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 212B (S)-1-(oxetan-3-yl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 212A for(S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate inEXAMPLE 168A.

Example 212C(S)-3-nitro-4-(1-(oxetan-3-yl)pyrrolidin-3-ylamino)benzenesulfonamide

The title compound was prepared by substituting4-fluoro-3-nitrobenzenesulfonamide for4-chloro-3-nitrobenzenesulfonamide and EXAMPLE 212B for4-methylpiperazin-1-amine dihydrochloride in EXAMPLE 6A.

Example 212D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3S)-1-oxetan-3-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 212C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.03 (s, 1H), 9.27(d, 1H), 8.58 (d, 1H), 8.42 (d, 1H), 8.37 (dd, 1H), 8.09 (d, 1H), 7.67(t, 1H), 7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.86 (d, 1H), 6.75(dd, 1H), 6.54 (d, 1H), 6.48 (dd, 1H), 4.67 (m, 4H), 4.09 (m, 1H), 3.59(m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.69 (m, 2H), 2.62 (dd, 1H), 2.28(m, 4H), 2.14 (m, 4H), 1.97 (s, 2H), 1.68 (m, 1H), 1.39 (t, 2H), 0.93(s, 6H).

Example 2134-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 213A4-((4-(2-(2-methoxyethoxy)ethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting2-(2′-methoxyethoxy)ethyl bromide for methyl iodide in EXAMPLE 134B.

Example 213B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 213A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 12.98 (s, 1H),9.26 (d, 1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 3.96-3.86 (m, 2H), 3.72 (dd, 1H), 3.67-3.61(m, 4H), 3.51 (t, 2H), 3.48-3.38 (m, 2H), 3.28 (s, 3H), 3.07 (m, 4H),2.95 (d, 1H), 2.77 (s, 2H), 2.70 (m, 1H), 2.60 (t, 2H), 2.30-2.05 (m,8H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2144-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 214A4-((4-(cyanomethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 2-bromoacetonitrile formethyl iodide in EXAMPLE 134B.

Example 214B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 214A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.01 (s, 1H),9.26 (d, 1H), 8.86 (t, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 3.93 (m, 1H), 3.87 (d, 1H), 3.77 (s, 2H),3.65 (dt, 1H), 3.51-3.40 (m, 2H), 3.07 (m, 4H), 2.87 (d, 1H), 2.77 (s,2H), 2.60 (d, 1H), 2.50 (m, 1H), 2.38 (t, 1H), 2.26 (m, 2H), 2.14 (m,4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2154-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 215A4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 2-dimethylaminoacetylchloride hydrochloride for methyl iodide in EXAMPLE 134B.

Example 215B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 215A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.27 (d, 1H), 8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (dd, 1H), 6.75 (d, 1H),6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H), 4.20 (dd, 1H), 3.95-3.76 (m,2H), 3.60-3.40 (m, 3H), 3.32 (dd, 1H), 3.25-3.12 (m, 2H), 3.07 (m, 4H),2.80 (m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23 (s, 2H), 2.14 (m, 4H),1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 216(2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholin-4-yl)aceticacid Example 216A tert-butyl2-(2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholino)acetate

The title compound was prepared by substituting tert-butyl2-bromoacetate for methyl iodide in EXAMPLE 134B.

Example 216B tert-butyl2-(2-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)methyl)morpholino)acetate

The title compound was prepared by substituting EXAMPLE 216A for EXAMPLE130C in EXAMPLE 130D.

Example 216C(2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholin-4-yl)aceticacid

The title compound was prepared by treating EXAMPLE 216B with 50%trifluoroacetic acid in dichloromethane. ¹H NMR (500 MHz, pyridine-d₅) δ12.97 (s, 1H), 9.26 (d, 1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.30 (dd, 1H),8.12 (d, 1H), 7.69 (t, 1H), 7.64 (d, 1H), 7.43 (d, 2H), 7.08 (d, 2H),6.88 (d, 1H), 6.76 (dd, 1H), 6.55 (d, 1H), 6.47 (m, 1H), 4.05-4.00 (m,1H), 3.91 (d, 1H), 3.79 (dt, 1H), 3.50 (s, 2H), 3.45 (m, 2H), 3.13 (d,1H), 3.07 (m, 4H), 2.88 (d, 1H), 2.78 (s, 2H), 2.57 (dt, 1H), 2.43 (t,1H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s,6H).

Example 2174-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 217A

The title compound was prepared by substituting EXAMPLE 134A fortert-butyl piperazine-1-carboxylate and 3-oxetanone for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 217B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 217A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (d, 1H), 8.87 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 4.64 (m, 4H), 3.93 (m, 1H), 3.89 (d, 1H),3.68 (dt, 1H), 3.53-3.35 (m, 3H), 3.07 (m, 4H), 2.77 (s, 2H), 2.72 (d,1H), 2.44 (d, 1H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.85 (t,1H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2184-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 218A4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 134A for EXAMPLE173A in EXAMPLE 173B.

Example 218B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 218A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (d, 1H), 8.88 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 3.88 (d, 1H), 3.84-3.81 (m, 1H), 3.59 (dt,1H), 3.50-3.40 (m, 2H), 3.07 (m, 4H), 2.93 (d, 1H), 2.77 (s, 2H), 2.69(d, 1H), 2.34 (dt, 1H), 2.26 (m, 2H), 2.21 (t, 1H), 2.14 (m, 4H), 1.97(s, 2H), 1.58 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H), 0.45-0.39 (m, 4H).

Example 2194-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 219A5-(methylthio)-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

A mixture of EXAMPLE 36B (0.1 g) and sodium methanethiolate (0.04 g) inN,N-dimethylformamide (2 mL) was heated at 80° C. overnight. Aftercooling, the reaction mixture was partitioned between water and ethylacetate. The organic layer was separated, and the aqueous layer wasextracted with additional ethyl acetate three times. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatography onsilica gel using 10-50% ethyl acetate in hexanes to provide the titlecompound.

Example 219B5-(methylsulfonyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

A mixture of EXAMPLE 219A (0.15 g) and 75% meta-chloroperoxybenzoic acid(0.217 g) in chloroform (4 mL) was stirred at room temperature. Thereaction mixture was stirred overnight. The reaction mixture was thenpartitioned between ethyl acetate and water. The organic layer wasseparated, and the aqueous layer was extracted with additional ethylacetate three times. The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash column chromatography on silica gel using 10-50% ethyl acetatein hexanes to provide the title compound.

Example 219C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-(methylsulfonyl)-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 219B for EXAMPLE11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.65 (s,1H), 8.81 (s, 1H), 8.55 (d, 1H), 8.01 (d, 1H), 7.55 (d, 1H), 7.49-7.50(m, 2H), 7.37 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.21(d, 1H), 4.36 (d, 2H), 3.88 (dd, 2H), 3.13 (s, 4H), 2.95 (s, 2H),2.36-2.38 (m, 2H), 2.03-2.16 (m, 4H), 1.97 (s, 3H), 1.66-1.69 (m, 2H),1.38-1.402 (m, 4H), 0.93 (s, 6H).

Example 2204-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 220A4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-(trifluoromethylsulfonyl)benzenesulfonamide

To a solution of EXAMPLE 37C (0.500 g) in tetrahydrofuran (5 mL) wasadded sodium hydride (0.596 g). Additional tetrahydrofuran (25 mL) wasadded and the mixture stirred for 30 minutes, then4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.145 g) wasadded as a solution in tetrahydrofuran (5 mL). After stirring for 2hours, the reaction mixture was partitioned between 1N aqueous HCl (50mL) and dichloromethane (200 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated. The resulting solid waschromatographed over silica gel (Reveleris 80 g) eluting with a gradientof 0.5% to 7.5% methanol/dichloromethane over 30 minutes (flow=40mL/min) to provide the title compound.

Example 220B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 220A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 8.42 (s, 1H), 8.35-8.22 (m, 1H),8.01 (s, 1H), 7.49 (d, 4H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (s, 1H),6.38 (s, 1H), 6.21 (s, 1H), 4.42 (d, 2H), 3.76 (s, 2H), 3.59 (s, 2H),3.10 (s, 6H), 2.15 (s, 6H), 2.02-1.74 (m, 6H), 1.40 (s, 2H), 0.93 (s,6H).

Example 2214-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 221A4-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting(4-methyltetrahydro-2H-pyran-4-yl)methanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 221B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 221A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.69 (s,1H), 8.36 (s, 1H), 8.04-8.06 (m, 2H), 7.50-7.53 (m, 3H), 7.41 (d, 1H),7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H),4.00 (s, 2H), 3.63-3.67 (m, 2H), 3.53-3.58 (m, 2H), 3.09 (s, 4H), 2.82(s, 2H), 2.27 (s, 2H), 2.15 (s, 2H), 1.58-1.63 (m, 2H), 1.39 (t, 2H),1.30-1.34 (m, 2H), 1.09 (s, 3H), 0.92 (s, 6H).

Example 222 ethyl4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)piperazine-1-carboxylateExample 222A ethyl 4-(2-nitro-4-sulfamoylphenyl)piperazine-1-carboxylate

The title compound was prepared by substituting ethylpiperazine-1-carboxylate for 1-(tetrahydropyran-4-yl)methylamine inEXAMPLE 1F.

Example 222B ethyl4-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)piperazine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 222A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.52 (br. s, 1H), 8.08 (d, 1H), 7.89 (d, 1H),7.59 (m, 2H), 7.43 (t, 1H), 7.35 (d, 2H), 7.23 (d, 1H), 7.05 (d, 2H),6.94 (d, 1H), 6.63 (dd, 1H), 6.29 (m, 2H), 4.07 (q, 2H), 3.47 (m, 4H),3.17 (d, 2H), 3.00 (m, 8H), 2.73 (s, 2H), 2.18 (m, 6H), 1.96 (s, 2H),1.39 (t, 2H), 1.20 (t, 3H), 0.93 (s, 6H).

Example 2234-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 223A

The title compound was prepared by substituting4-(piperidin-4-yl)morpholine for 1-(tetrahydropyran-4-yl)methylamine inEXAMPLE 1F.

Example 223B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 223A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.53 (br. s, 1H), 8.05 (d, 1H), 7.91 (d, 1H),7.58 (m, 2H), 7.43 (t, 1H), 7.35 (d, 2H), 7.26 (d, 1H), 7.05 (d, 2H),6.91 (d, 1H), 6.62 (dd, 1H), 6.29 (m, 2H), 5.76 (s, 1H), 3.57 (m, 4H),3.20 (m, 2H), 3.01 (m, 4H), 2.80 (t, 2H), 2.73 (s, 2H), 2.47 (m, 4H),2.32 (m, 1H), 2.18 (m, 6H), 1.96 (m, 3H), 1.82 (m, 2H), 1.44 (m, 4H),0.93 (s, 6H).

Example 2244-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 224A (R)-tert-butyl 1-(oxetan-3-yl)pyrrolidin-3-ylcarbamate

The title compound was prepared by substituting (R)-tert-butylpyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate and3-oxetanone for 4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 224B (R)-1-(oxetan-3-yl)pyrrolidin-3-amine

The title compound was prepared by substituting EXAMPLE 224A for(S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate inEXAMPLE 168A.

Example 224C(R)-3-nitro-4-(1-(oxetan-3-yl)pyrrolidin-3-ylamino)benzenesulfonamide

The title compound was prepared by substituting4-fluoro-3-nitrobenzenesulfonamide for4-chloro-3-nitrobenzenesulfonamide and EXAMPLE 224B for4-methylpiperazin-1-amine dihydrochloride in EXAMPLE 6A.

Example 224D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 224C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, pyridine-d₅) δ 13.03 (s, 1H), 9.26(d, 1H), 8.57 (d, 1H), 8.42 (d, 1H), 8.36 (dd, 1H), 8.09 (d, 1H), 7.66(m, 1H), 7.64 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.86 (d, 1H), 6.75(dd, 1H), 6.54 (d, 1H), 6.48 (dd, 1H), 4.67 (m, 4H), 3.58 (m, 1H), 3.07(m, 4H), 2.77 (m, 2H), 2.68 (m, 2H), 2.61 (m, 1H), 2.28 (m, 4H), 2.14(m, 4H), 1.97 (m, 2H), 1.67 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 2254-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 225A(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

To EXAMPLE 207A (0.217 g) and4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (0.281 g) intetrahydrofuran (5 mL) was added diisopropylethylamine (0.559 mL) andthe reaction was allowed to stir at room temperature for 1 hour and wasthen heated to 50° C. for 1 hour. The reaction was concentrated, theresidue was loaded onto silica gel (Reveleris 40 g) and eluted with agradient of 0.75% methanol/dichloromethane to 7.5%methanol/dichloromethane to provide the title compound.

Example 225B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 225A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.52-11.23 (m, 1H), 8.17 (d,1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.54 (d, 1H), 7.53-7.50 (m, 1H), 7.48(d, 1H), 7.34 (d, 2H), 7.10-6.97 (m, 4H), 6.67 (d, 1H), 6.40 (dd, 1H),6.18 (d, 1H), 4.60 (dd, 4H), 4.20 (s, 1H), 3.11-2.63 (m, 12H), 2.19 (d,6H), 1.95 (s, 2H), 1.58 (s, 1H), 1.40 (d, 2H), 0.92 (s, 6H).

Example 2264-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 226A tert-butyl4-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)piperidine-1-carboxylate

To a solution of EXAMPLE 82 (800 mg) and tert-butyl4-aminopiperidine-1-carboxylate (203 mg) in dioxane (10 mL) was addedHunig's Base (1 mL). The mixture was stirred at 120° C. overnight. Themixture was diluted with ethyl acetate (200 mL) and washed with water,brine and dried over Na₂SO₄. After filtration and evaporation ofsolvent, the residue was loaded on a silica gel cartridge and elutedwith 3% methanol in dichloromethane to give the title compound.

Example 226B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylamino)phenylsulfonyl)benzamide

To a solution of EXAMPLE 226A (902 mg) in dichloromethane (10 mL) wasadded trifluoroacetic acid (5 mL). The mixture was stirred at roomtemperature for 3 hours. The mixture was concentrated under vacuum andco-concentrated with dichloromethane twice to afford the crude productwhich was used in the next step without further purification.

Example 226C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a solution of EXAMPLE 226B (79 mg) in tetrahydrofuran (3 mL) andacetic acid (1 mL) was added acetone (54 mg) and MP-cyanoborohydride(150 mg, 2.25 mmol/g). The mixture was stirred overnight. The mixturewas filtered. The filtrate was concentrated and the residue was loadedon a silica gel cartridge and eluted with 5 to 10% 7N NH₃ in methanol indichloromethane to provide the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.09 (s, 1H), 8.34 (m, 1H), 7.93 (m, 2H), 7.66(m, 4H), 7.35 (d, 2H), 7.06 (d, 2H), 6.89 (m, 1H), 6.74 (dd, 1H), 6.59(dd, 1H), 6.50 (d, 1H), 3.11 (m, 6H), 2.73 (m, 4H), 2.26 (m, 9H), 1.97(s, 3H), 1.40 (t, 2H), 1.23 (s, 8H), 0.94 (s, 6H).

Example 227N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 227A 1-tert-butylpiperidin-4-amine

To a solution of 1-tert-butylpiperidin-4-one (5.0 g) in methanol (100mL) and water (10 mL) was added ammonium formate (20.3 g) and 0.5 g ofPd/C (10%). The mixture was stirred overnight. The mixture was filteredand the filtrate was concentrated under vacuum and the residue wasdiluted with ethyl acetate (500 mL) and washed with water and brine.After drying over Na₂SO₄ and filtration, the solvent was evaporatedunder vacuum to provide the title compound.

Example 227B4-(1-tert-butylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

To a mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.2 g) and EXAMPLE227A (1.56 g) in tetrahydrofuran (20 mL) was added Hunig's Base (6 mL).The mixture was stirred for 3 days. The mixture was diluted with ethylacetate (300 mL) and water (100 mL) and stirred until the soliddisappeared into the solution. The layers were separated and the organicphase was washed with water and brine, dried over Na₂SO₄, and filtered.The combined aqueous layers were extracted again with ethyl acetate andthe combined organic phases were dried over Na₂SO₄. After filtration,the solvent was evaporated to provide the title compound.

Example 227CN-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 227B for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.51 (s, 1H), 8.43 (d, 1H), 8.04 (m, 1H), 7.93(d, 1H), 7.72 (m, 1H), 7.56 (dd, 1H), 7.42 (m, 1H), 7.34 (m, 3H), 7.05(d, 2H), 6.93 (dd, 1H), 6.62 (dd, 1H), 6.28 (m, 1H), 3.04 (m, 6H), 2.73(s, 3H), 2.25 (m, 9H), 1.95 (s, 2H), 1.68 (m, 2H), 1.32 (m, 9H), 0.93(s, 6H).

Example 2284-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(2-methoxyethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 228A tert-butyl3-((2-nitro-4-sulfamoylphenylamino)methyl)piperidine-1-carboxylate

The title compound was prepared by substituting tert-butyl3-(aminomethyl)piperidine-1-carboxylate for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 228B 3-nitro-4-(piperidin-3-ylmethylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 228A for EXAMPLE113A in EXAMPLE 134A.

Example 228C4-((1-(2-methoxyethyl)piperidin-3-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 228B for EXAMPLE134A and 2-methoxyethyl bromide for methyl iodide in EXAMPLE 134B.

Example 228D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(2-methoxyethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 228C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅, 90° C.) δ 12.40 (s,1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.20 (m, 2H), 7.95 (bs, 1H), 7.80 (s,1H), 7.46 (d, 1H), 7.36 (d, 2H), 7.07 (d, 2H), 7.05 (s, 1H), 6.75 (d,1H), 6.59 (s, 1H), 6.47 (s, 1H), 3.65-3.50 (m, 5H), 3.20 (s, 3H), 3.04(m, 5H), 2.81 (s, 3H), 2.74 (m, 1H), 2.24 (m, 7H), 2.06 (s, 2H), 2.00(s, 2H), 1.75 (m, 1H), 1.57 (m, 2H), 1.42 (t, 2H), 1.15 (m, 1H), 0.95(s, 6H).

Example 2294-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 229A4-((1-(cyanomethyl)piperidin-3-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 228B for EXAMPLE134A and 2-bromoacetonitrile for methyl iodide in EXAMPLE 134B.

Example 229B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[1-(cyanomethyl)piperidin-3-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 229A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H),9.03 (s, 1H), 8.42 (s, 1H), 8.30 (d, 1H), 8.10 (d, 1H), 7.68 (m, 2H),7.44 (d, 2H), 7.08 (m, 3H), 6.99 (d, 1H), 6.75 (d, 1H), 6.51 (m, 2H),3.78 (m, 2H), 3.43 (d, 1H), 3.13 (m, 1H), 3.04 (m, 4H), 2.76 (s, 2H),2.71-2.65 (m, 3H), 2.52 (m, 1H), 2.25 (m, 2H), 2.14 (m, 4H), 1.97 (s,2H), 1.84 (m, 1H), 1.68 (m, 1H), 1.50 (m, 2H), 1.39 (t, 2H), 1.07-0.99(m, 1H), 0.93 (s, 6H).

Example 2304-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 230A4-((4-fluoro-1-methylpiperidin-4-yl)methoxy)-3-(trifluoromethylsulfonyl)benzenesulfonamide

To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol (0.315 g) intetrahydrofuran (5 mL) was added sodium hydride (0.342 g). Afterstirring for 15 minutes,4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (0.658 g) wasadded as a solution in tetrahydrofuran (2 mL) followed by additionaltetrahydrofuran (5 mL). After stirring for 1 hour, the reaction waspoured in dichloromethane (50 mL) and water (25 mL) and the pH of thewater layer was adjusted to 8. The organic layer was dried overmagnesium sulfate, filtered, and concentrated. The resulting oil waschromatographed over silica gel (Reveleris 40 g) eluting with a gradientof 1.0% to 10% 7N NH₃ in methanol/dichloromethane over 20 minutes thenmaintaining 10% 7N NH₃ in methanol/dichloromethane for 5 minutes(flow=30 mL/min) to provide the title compound.

Example 230B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 230A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.63-11.57 (m, 1H), 8.40-8.36 (m, 1H),8.28-8.17 (m, 1H), 7.97 (s, 1H), 7.53 (d, 1H), 7.50-7.32 (m, 5H), 7.05(d, 1H), 7.05 (d, 1H), 6.68-6.61 (m, 1H), 6.35 (s, 1H), 6.22 (s, 1H),4.55-4.40 (m, 2H), 3.06 (s, 8H), 2.79 (s, 4H), 2.06 (d, 13H), 1.39 (s,2H), 0.93 (s, 6H).

Example 231N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 231A(R)-5-chloro-6-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)pyridine-3-sulfonamide

To EXAMPLE 207A (0.051 g) and EXAMPLE 40A (0.049 g) in dioxane (5 mL)was added diisopropylethylamine (0.131 mL) and the reaction was heatedto 75° C. for 1 hour then 85° C. for 2 days. The reaction wasconcentrated, loaded onto silica gel (Reveleris 12 g) and eluted with agradient of 0.75% methanol/dichloromethane to 7.5%methanol/dichloromethane to provide the title compound.

Example 231BN-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 231A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.71 (s, 1H), 11.44-11.11 (m, 1H), 8.44 (d,1H), 8.07 (d, 1H), 7.90 (d, 1H), 7.61 (d, 1H), 7.52 (dd, 2H), 7.34 (d,2H), 7.19 (s, 1H), 7.04 (d, 2H), 6.67 (d, 1H), 6.42 (dd, 1H), 6.16 (s,1H), 4.77-4.39 (m, 5H), 3.19-2.63 (m, 11H), 2.19 (s, 7H), 1.91 (d, 3H),1.38 (s, 2H), 0.92 (s, 6H).

Example 232 tert-butyl4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]piperazine-1-carboxylateExample 232A tert-butyl 4-nitrosopiperazine-1-carboxylate

In a 500 mL round-bottomed flask, 6N aqueous HCl (30 mL) was cooled to−10° C., and tert-butyl piperazine-1-carboxylate (10 g) was added.Sodium nitrite (4.5 g) dissolved in 35 ml water was added slowly. NaOH(10 g in 20 mL water) was used to neutralize the solution.Dichloromethane (3×50 mL) was used to extract the product. After dryingover Na₂SO₄ and filtration, the solution was concentrated. The crudeproduct was added to a silica gel column (Analogix, SF65-400 g,) andpurified by eluting with 0-30% ethyl acetate in hexane.

Example 232B tert-butyl 4-aminopiperazine-1-carboxylate

In a 100 mL round-bottomed flask was added EXAMPLE 232A (0.15 g) andzinc (1 g) in water/methanol (1:1, 10 mL) to give a suspension. Themixture was cooled to 0° C. 12N Aqueous HCl (2 ml) was added slowly, andthe mixture was stirred at 0° C. for 30 minutes. 2N Aqueous NaOHsolution was used to adjust the mixture to basic pH. The mixture wasfiltered, and extracted with ether (3×30 mL). After drying over Na₂SO₄,filtration, and concentration, the crude product was added to a silicagel column (Analogix, SF15-12 g,) and purified by eluting with 0-25%ethyl acetate in hexane.

Example 232C tert-butyl4-(2-nitro-4-sulfamoylphenylamino)piperazine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 232B for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 232D tert-butyl4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]piperazine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 232C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.47 (br. s, 1H), 8.86 (s, 1H), 8.34 (d, 1H),7.90 (d, 1H), 7.59 (m, 2H), 7.36 (m, 4H), 7.23 (m, 1H), 7.05 (d, 2H),6.61 (dd, 1H), 6.27 (m, 2H), 2.99 (m, 5H), 2.76 (m, 6H), 2.19 (m, 6H),1.96 (s, 2H), 1.41 (m, 11H), 1.24 (m, 4H), 0.93 (s, 6H).

Example 2334-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-(pentafluoro-lambda˜6˜-sulfanyl)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 233A 2-(5-bromo-2-nitrophenyl)sulfur pentafluoride

To a solution of 3-bromophenylsulfur pentafluoride (2.18 g) inconcentrated H₂SO₄ (5 mL) was added KNO₃ (780 mg). The mixture wasstirred overnight. The mixture was diluted with diethyl ether (100 mL)and washed with water and brine. After drying over Na₂SO₄ andfiltration, the solvent was evaporated under vacuum to provide the titlecompound.

Example 233B 2-(5-bromo-2-aminophenyl)sulfur pentafluoride

EXAMPLE 233A (6.4 g) and tetrahydrofuran (300 mL) were added to Ra—Ni,(12.80 g) in a 50 mL pressure bottle and the mixture stirred for 2 hoursat 30 psi and room temperature. The mixture was filtered through a nylonmembrane and the filtrate was concentrated under vacuum to provide thetitle compound.

Example 233C4-bromo-2-pentafluorosulfanyl-N-(tetrahydro-2H-pyran-4-ylmethyl)aniline

To a solution of EXAMPLE 233B (4.4 g) in methanol (50 mL) was addedtetrahydro-2H-pyran-4-carbaldehyde (1.68 g) and decaborane (1.1 g). Themixture was stirred and monitored by thin layer chromatography. Moretetrahydro-2H-pyran-4-carbaldehyde (500 mg) was added to the stirringmixture to drive the reaction to completion. The reaction mixture wasconcentrated under vacuum and ethyl acetate (500 mL) and brine (200 mL)were added. The organic phase was dried over Na₂SO₄. Filtration andevaporation of the solvent and flash chromatography (20% ethyl acetatein hexane) gave the title compound.

Example 233D4-thioacetoxy-2-pentafluorosulfanyl-N-(tetrahydro-2H-pyran-4-ylmethyl)aniline

To a solution of EXAMPLE 233C (456 mg) and potassium ethanethioate (197mg) in dioxane (4 mL) was added tris(dibenzylideneacetone)dipalladium(0)(27 mg) and xantphos (33 mg) followed by N,N-diisopropylethylamine (0.5mL). The mixture was purged with argon, sealed and stirred undermicrowave irradiation for 60 minutes at 120° C. The mixture wasdissolved in ethyl acetate (300 mL) and water (100 mL). The organicphase was washed with brine and dried over Na₂SO₄. Filtration andevaporation of the solvent followed by flash chromatography (20% ethylacetate in hexane) provided the title compound.

Example 233E3-pentafluorosulfanyl-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenylsulfonamide

N-chlorosuccinimide (527 mg) was added to a mixture of 2N aqueous HCl(1.5 mL) and acetonitrile (12 mL) and then cooled to 0° C. A solution ofEXAMPLE 233D (386 mg) in acetonitrile (3 mL) was added to the mixturewhich was then stirred at 0° C. for 2 hours, and then diluted with ethylacetate (300 mL) and washed with brine and dried over Na₂SO₄. Afterfiltration and evaporation of solvent, the residue was dissolved inisopropyl alcohol (20 mL) and cooled to 0° C. with stirring. Then,ammonium hydroxide (conc. 10 mL) was added to mixture. After stirringfor 2 hours, the mixture was concentrated under vacuum and the residuewas added to ethyl acetate (400 mL) and water (150 mL). The organiclayer was washed with brine and dried over Na₂SO₄. After filtration andevaporation of solvent, the residue was purified by flash column (20%ethyl acetate in dichloromethane) to provide the title compound.

Example 233F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-(pentafluoro-lambda˜6˜-sulfanyl)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 233E for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.71 (s, 1H), 11.33 (m, 1H), 8.12 (m, 2H), 7.72(d, 1H), 7.54 (m, 3H), 7.33 (m, 2H), 7.02 (m, 3H), 6.67 (m, 2H), 6.42(m, 1H), 6.16 (d, 1H), 3.82 (m, 2H), 3.21 (m, 4H), 3.05 (m, 4H), 2.73(s, 2H), 2.21 (m, 8H), 1.97 (m, 3H), 1.29 (m, 4H), 0.92 (s, 6H).

Example 2344-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 234A 4-vinyltetrahydro-2H-pyran-4-ol

Dihydro-2H-pyran-4(3H)-one (8.01 g) in anhydrous ethyl ether (50 mL) wastreated with 1.0 M vinylmagnesium bromide (104 mL) over 20 minutes at 0°C. The reaction mixture was stirred at room temperature overnight. Thereaction was quenched with saturated NH₄Cl, and the organic layer wasseparated. The aqueous layer was extracted with additional ethyl etherthree times. The combined organic layers were washed with brine, dried,filtered, and concentrated. The residue was purified by flash columnchromatography on silica gel using 20% ethyl acetate in hexanes toprovide the title compound.

Example 234B 4-methoxy-4-vinyltetrahydro-2H-pyran

To a solution of EXAMPLE 234A (9.4 g) in tetrahydrofuran (150 mL) wasadded 60% sodium hydride (5.28 g) at 0° C. portionwise. After theaddition was complete, the solution was heated under reflux for threehours. After cooling, to this suspension was added dimethyl sulfate(8.41 mL) slowly. The solution was heated under reflux overnight, cooledto room temperature, and hydrolyzed with cool saturated aqueous NH₄Cl.After extraction with diethyl ether several times, the combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatograph onsilica gel using 1-10% ethyl acetate in hexanes to provide the titlecompound.

Example 234C 4-methoxytetrahydro-2H-pyran-4-carbaldehyde

EXAMPLE 234B (4.3 g) in tetrahydrofuran (200 mL) and water (67 mL) wastreated with 4% osmium tetroxide in water (9.24 mL). To this solutionwas added potassium periodate (13.91 g) portionwise over 2 hours. Thesolution was stirred overnight at room temperature. Water was added tothe mixture followed by repeat extractions with diethyl ether. Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatography onsilica gel using 5-20% ethyl acetate in hexanes to provide the titlecompound.

Example 234D (4-methoxytetrahydro-2H-pyran-4-yl)methanol

EXAMPLE 234C (1.8 g) in 2-propanol (28 mL) and water (7 mL) was cooledto 0° C. To this solution was added sodium borohydride (0.709 g). Thesolution was stirred and allowed to warm to room temperature over 3hours. The reaction was quenched with acetone, and stirred for another 1hour. The clear liquid was separated from solid by decanting. Additionalethyl acetate was used to wash the solid, and was the mixture wasdecanted. The combined organic solutions were concentrated. The residuewas purified by flash chromatography on silica gel eluting 1:1 ethylacetate:hexane to provide the title compound.

Example 234E4-((4-methoxytetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 234D for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 234F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methoxytetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 234E for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.68 (s,1H), 8.36 (s, 1H), 8.04-8.07 (m, 2H), 7.50-7.53 (m, 3H), 7.45 (d, 1H),7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H),4.21 (s, 2H), 3.65-3.67 (m, 2H), 3.53-3.56 (m, 2H), 3.19 (s, 3H), 3.10(s, 4H), 2.86 (s, 2H), 2.30 (s, 4H), 2.15 (s, 2H), 1.96 (s, 2H),1.61-1.74 (m, 4H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 2354-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 235A (R)-tert-butyl3-(2-nitro-4-sulfamoylphenoxy)pyrrolidine-1-carboxylate

The title compound was prepared by substituting (R)-tert-butyl3-hydroxypyrrolidine-1-carboxylate for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 235B (R)-tert-butyl3-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenoxy)pyrrolidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 235A for EXAMPLE 1F in EXAMPLE 1G.

Example 235C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a solution of EXAMPLE 235B (0.230 g) in dichloromethane (3 mL) wasadded trifluoroacetic acid (0.377 mL). After stirring for 4 hours, thereaction was concentrated then dissolved in dichloromethane (3 mL) andtreated with 1,3-difluoropropan-2-one (0.028 g) followed by sodiumtriacetoxyborohydride (0.078 g). After stirring for 4 hours, thereaction was quenched by the addition of saturated aqueous NaHCO₃ anddichloromethane (5 mL). The reaction was diluted with dichloromethane(250 mL) and saturated aqueous NaHCO₃ (100 mL) was added. The organiclayer was separated, washed with brine (100 mL), dried over magnesiumsulfate, filtered and concentrated. Trituration with acetonitrile gavethe title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.34 (s, 1H), 8.03 (s, 2H), 7.52 (d, 3H), 7.35 (d, 3H), 7.04 (d,2H), 6.75-6.60 (m, 1H), 6.40 (s, 1H), 6.20 (s, 1H), 5.17-5.06 (m, 1H),4.60 (d, 4H), 2.98 (d, 12H), 2.37-2.02 (m, 6H), 1.96 (s, 3H), 1.39 (s,2H), 0.93 (s, 6H).

Example 2364-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(oxetan-3-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 236A2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperazin-1-ylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 232D for EXAMPLE1A in EXAMPLE 1B.

Example 236B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(oxetan-3-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 236A fortert-butyl piperazine-1-carboxylate and oxetan-3-one for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.67 (br. s, 1H), 9.20 (s, 1H), 8.53 (d, 1H),8.04 (d, 1H), 7.83 (dd, 1H), 7.53 (m, 4H), 7.34 (d, 2H), 7.04 (d, 2H),6.67 (dd, 1H), 6.39 (m, 1H), 6.18 (d, 1H), 4.55 (t, 2H), 4.44 (t, 2H),3.47 (m, 1H), 3.06 (m, 4H), 2.88 (m, 4H), 2.74 (m, 4H), 2.09 (m, 11H),1.38 (t, 2H), 0.91 (s, 6H).

Example 2374-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 236A fortert-butyl piperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹H NMR (400 MHz,pyridine-d₅) δ 13.05 (br. s, 1H), 9.27 (d, 1H), 9.23 (s, 1H), 8.44 (m,2H), 8.12 (d, 1H), 7.68 (m, 3H), 7.44 (m, 2H), 7.06 (m, 2H), 6.75 (dd,1H), 6.51 (m, 2H), 4.02 (m, 2H), 3.31 (m, 2H), 3.06 (m, 4H), 2.91 (m,5H), 2.76 (s, 2H), 2.38 (m, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s,2H), 1.65 (m, 2H), 1.39 (m, 7H), 0.93 (s, 6H).

Example 2384-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3R)-tetrahydrofuran-3-ylamino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 238A (R)-3-nitro-4-(tetrahydrofuran-3-ylamino)benzenesulfonamide

The title compound was prepared by substituting(R)-tetrahydrofuran-3-amine for 4-methylpiperazin-1-aminedihydrochloride in EXAMPLE 6A.

Example 238B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3R)-tetrahydrofuran-3-ylamino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 238A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.59 (s, 1H), 8.47 (d, 1H), 8.19 (m, 2H), 7.97(d, 1H), 7.74 (m, 1H), 7.52 (d, 1H), 7.46 (t, 1H), 7.34 (m, 2H), 7.05(m, 2H), 6.96 (d, 1H), 6.89 (d, 1H), 6.65 (dd, 1H), 6.33 (m, 1H), 6.22(d, 1H), 4.31 (m, 1H), 3.92 (m, 1H), 3.87 (m, 1H), 3.76 (m, 1H), 3.69(m, 1H), 3.04 (m, 4H), 2.73 (m, 2H), 2.33 (m, 1H), 2.18 (m, 6H), 1.95(m, 2H), 1.88 (m, 1H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 2394-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 239A tert-butyl (4,4-difluorocyclohexyl)methylcarbamate

Tert-butyl (4-oxocyclohexyl)methylcarbamate (5 g) and diethylaminosulfurtrifluoride (7.45 g) were stirred in dichloromethane (100 mL) for 24hours. The mixture was quenched with pH 7 buffer (100 mL), and pouredinto ether (400 mL). The resulting solution was separated, and theorganic layer was washed twice with water, and once with brine, and thenconcentrated to give the crude product and fluoroolefin by-product in a3:2 ratio. The crude material was taken up in tetrahydrofuran (70 mL)and water (30 mL), and N-methylmorpholine-N-oxide (1.75 g), and OsO₄(2.5 wt % solution in t-butanol) were added, and the mixture was stirredfor 24 hours. Na₂S₂O₃ (10 g) was then added, and the mixture was stirredfor 30 minutes. The mixture was then diluted with ether (300 mL), andthe resulting solution was separated, and rinsed twice with water, andonce with brine, and concentrated. The crude product was chromatographedon silica gel using 5-10% ethyl acetate in hexanes to provide the titlecompound.

Example 239B (4,4-difluorocyclohexyl)methanamine

A solution of EXAMPLE 239A (3 g) in dichloromethane (35 mL),trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for2 hours. The solution was concentrated, then concentrated from toluene,and left on high vacuum for 24 hours. The semi-solid was taken up inether/hexane and filtered to provide the title compound as itstrifluoroacetic acid salt.

Example 239C4-((4,4-difluorocyclohexyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 239B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 239D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 239C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.40 (s, 1H), 11.61 (br s, 1H), 8.53 (m, 1H),8.50 (d, 1H), 7.99 (d, 1H), 7.73 (d, 1H), 7.49 (m, 2H), 7.32 (d, 2H),7.04 (d, 2H), 7.00 (d, 1H), 6.65 (d, 1H), 6.32 (s, 1H), 6.21 (s, 1H),3.37 (m, 4H), 3.06 (m, 4H), 2.73 (m, 2H), 2.18 (m, 4H), 1.97 (m, 4H),1.81 (m, 4H), 1.38 (m, 2H), 1.20 (m, 4H), 0.92 (s, 6H).

Example 240N-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 240A4-(1-tert-butylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

To a mixture of 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide(307 mg) and EXAMPLE 227A (156 mg) in tetrahydrofuran (4 mL) was addedHunig's Base (1 mL). The mixture was stirred for 3 days. The mixture wasdiluted with ethyl acetate (300 mL) and water (100 mL) and stirred untilthe solid disappeared into the solution. The layers were separated andthe organic phase was washed with water, brine and dried over Na₂SO₄.After filtration, the combined aqueous layers were extracted again withethyl acetate and the combined organic phase was dried over Na₂SO₄.After filtration, the solvent was evaporated to provide the titlecompound.

Example 240BN-({4-[(1-tert-butylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 240A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.53 (s, 1H), 8.04 (s, 1H), 7.94 (d, 1H), 7.86(m, 1H), 7.55 (d, 2H), 7.44 (d, 1H), 7.33 (m, 3H), 7.05 (d, 2H), 6.92(m, 1H), 6.62 (dd, 1H), 6.43 (m, 1H), 6.29 (d, 2H), 3.79 (m, 1H), 3.05(m, 6H), 2.73 (s, 3H), 2.19 (m, 8H), 1.96 (s, 3H), 1.27 (m, 12H), 0.92(s, 6H).

Example 2414-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 241A tert-butyl2-((4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting tert-butyl2-(aminomethyl)morpholine-4-carboxylate for(tetrahydropyran-4-yl)methylamine and4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.

Example 241B tert-butyl2-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 241A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G.

Example 241C2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(morpholin-2-ylmethylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 241B for EXAMPLE1A in EXAMPLE 1B.

Example 241D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-({[4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 241C fortert-butyl piperazine-1-carboxylate and oxetan-3-one for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.92(dd, 1H), 7.54 (d, 1H), 7.51 (t, 1H), 7.48 (d, 1H), 7.34 (d, 2H), 7.25(m, 1H), 7.04 (m, 3H), 6.68 (dd, 1H), 6.41 (m, 1H), 6.19 (d, 1H), 4.54(t, 2H), 4.43 (m, 2H), 3.85 (m, 1H), 3.69 (m, 1H), 3.52 (m, 1H), 3.48(m, 1H), 3.39 (m, 2H), 3.07 (m, 4H), 2.77 (br s, 2H), 2.69 (d, 1H), 2.56(d, 1H), 2.21 (br s, 4H), 2.15 (t, 2H), 1.94 (m, 3H), 1.76 (t, 1H), 1.38(t, 2H), 0.92 (s, 6H).

Example 242N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 242A5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 138D.

Example 242BN-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 242A for EXAMPLE11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.71 (s,1H), 8.41 (d, 1H), 8.07 (d, 1H), 7.93 (d, 1H), 7.60 (d, 1H), 7.51-7.53(m, 2H), 7.40 (s, 1H), 7.33-7.35 (m, 2H), 7.03-7.05 (m, 2H), 6.68 (dd,1H), 6.42 (dd, 1H), 6.16 (d, 1H), 3.77 (d, 1H), 3.69-3.71 (m, 3H),3.48-3.53 (m, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.14-2.20 (m, 6H), 1.96(s, 2H), 1.65-1.76 (m, 4H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 243N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 243A5-chloro-6-(1-cyclopropylpiperidin-4-ylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 40A for4-chloro-3-nitrobenzenesulfonamide, 1-cyclopropylpiperidin-4-amine for4-methylpiperazin-1-amine dihydrochloride and Hunig's base forN¹,N¹,N²,N²-tetramethylethane-1,2-diamine in EXAMPLE 6A.

Example 243BN-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 243A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.40 (d, 1H), 8.05 (d, 1H), 7.88 (d, 1H), 7.56 (d, 1H), 7.50 (m,2H), 7.34 (d, 2H), 7.03 (d, 2H), 6.97 (br d, 1H), 6.66 (dd, 1H), 6.40(m, 1H), 6.16 (d, 1H), 4.04 (m, 1H), 3.03 (br m, 6H), 2.73 (s, 2H), 2.42(br m, 2H), 2.18 (br m, 6H), 1.95 (s, 2H), 1.80 (m, 3H), 1.62 (m, 2H),1.38 (t, 2H), 0.91 (s, 6H), 0.47 (m, 2H), 0.40 (br m, 2H).

Example 244N-[(5-chloro-6-{[(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 244A (S)-tert-butyl2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting (S)-tert-butyl2-(hydroxymethyl)-morpholine-4-carboxylate fortetrahydro-2H-pyran-4-yl-methanol and EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 244B(S)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 244A for EXAMPLE113A in EXAMPLE 134A.

Example 244C(S)-5-chloro-6-((4-(cyanomethyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 244B for EXAMPLE134A and 2-bromoacetonitrile for methyl iodide in EXAMPLE 134B.

Example 244DN-[(5-chloro-6-{[(2S)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 244C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 12.99 (s, 1H),9.09 (d, 1H), 8.70 (d, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.66 (m, 2H),7.44 (d, 2H), 7.07 (d, 2H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.48 (m, 1H),4.55 (dd, 1H), 4.43 (dd, 1H), 4.05 (m, 1H), 3.85 (d, 1H), 3.76 (s, 2H),3.63 (dt, 1H), 3.06 (m, 4H), 2.91 (d, 1H), 2.77 (s, 2H), 2.58 (d, 1H),2.51-2.44 (m, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t,2H), 0.94 (s, 6H).

Example 245N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 245A(S)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 244B for EXAMPLE134A and 2-(dimethylamino)acetyl chloride hydrochloride for methyliodide in EXAMPLE 134B.

Example 245BN-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 245A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.09 (d, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 8.11 (t, 1H), 7.66 (m, 2H),7.44 (d, 2H), 7.07 (d, 2H), 6.76 (s, 1H), 6.54 (s, 1H), 6.49 (s, 1H),4.85-4.46 (m, 3H), 4.45-3.87 (m, 3H), 3.50 (m, 1H), 3.37 (dd, 1H), 3.21(m, 2H), 3.07 (m, 4H), 2.86 (t, 1H), 2.77 (s, 2H), 2.27 (m, 8H), 2.14(m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 246N-[(5-chloro-6-{[(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 246A (R)-tert-butyl2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting (R)-tert-butyl2-(hydroxymethyl)-morpholine-4-carboxylate fortetrahydro-2H-pyran-4-yl-methanol and EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 246B(R)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 246A for EXAMPLE113A in EXAMPLE 134A.

Example 246C(R)-5-chloro-6-((4-(cyanomethyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 246B for EXAMPLE134A and 2-bromoacetonitrile for methyl iodide in EXAMPLE 134B.

Example 246DN-[(5-chloro-6-{[(2R)-4-(cyanomethyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 246C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 12.99 (s, 1H),9.09 (d, 1H), 8.70 (d, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.66 (m, 2H),7.44 (d, 2H), 7.07 (d, 2H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.48 (m, 1H),4.55 (dd, 1H), 4.43 (dd, 1H), 4.05 (m, 1H), 3.85 (d, 1H), 3.76 (s, 2H),3.63 (dt, 1H), 3.06 (m, 4H), 2.91 (d, 1H), 2.77 (s, 2H), 2.58 (d, 1H),2.51-2.44 (m, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t,2H), 0.94 (s, 6H).

Example 247N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 247A(R)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 246B for EXAMPLE134A and 2-(dimethylamino)acetyl chloride hydrochloride for methyliodide in EXAMPLE 134B.

Example 247BN-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 247A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.09 (d, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 8.11 (t, 1H), 7.66 (m, 2H),7.44 (d, 2H), 7.07 (d, 2H), 6.76 (s, 1H), 6.54 (s, 1H), 6.49 (s, 1H),4.85-4.46 (m, 3H), 4.45-3.87 (m, 3H), 3.50 (m, 1H), 3.37 (dd, 1H), 3.21(m, 2H), 3.07 (m, 4H), 2.86 (t, 1H), 2.77 (s, 2H), 2.27 (m, 8H), 2.14(m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2484-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 248A5-bromo-3-fluoro-2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine

The title compound was prepared by substituting5-bromo-2,3-difluoropyridine for 4-fluoro-3-nitrobenzenesulfonamide andEXAMPLE 37C for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 248B tert-butyl5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-ylcarbamate

EXAMPLE 248A (0.308 g), tert-butyl carbamate (0.141 g), palladium(II)acetate (0.011 g), Xantphos (0.043 g) and cesium carbonate (0.489 g)were combined with dioxane (5.0 mL) in a 20-mL vial equipped with amagnetic stir bar. The vial was flushed with nitrogen, capped andstirred at 100° C. overnight. Additional palladium(II) acetate (0.011g), Xantphos (0.043 g) and tert-butyl carbamate (0.141 g) were added andheating was continued at 100° C. for 8 hours. The cooled reactionmixture was diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), filtered and concentrated. The concentrate waschromatographed on silica gel with 7-25% ethyl acetate in hexanes as theeluent.

Example 248C5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonylchloride

Under ice-cooling, thionyl chloride (1.563 mL) was added dropwise over20 minutes to water (9 mL). The mixture was stirred for 12 hours to givea SO₂-containing solution. Separately, EXAMPLE 248B (0.295 g) was addedto a mixture of 1,4-dioxane (3.2 mL) and concentrated HCl (8 mL) at 0°C. After stirring for 15 minutes, a solution of sodium nitrite (0.065 g)in water (2 mL) was added dropwise and stirring was continued at 0° C.for 3 hours. Copper(I) chloride (0.042 g) and then the freshly preparedsolution of diazotized material were added sequentially to thepreviously prepared SO₂-containing solution. The resulting solution wasstirred for 30 minutes and then extracted with ethyl acetate (2×125 mL).The combined extracts were dried (MgSO₄), filtered and concentrated. Theconcentrate was chromatographed on silica gel with 5% ethyl acetate inhexanes as the eluent.

Example 248D5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 248C (0.08 g) in isopropanol (2 mL) at 0° C. was treated withammonium hydroxide (1.697 mL), stirred overnight and then concentratedto dryness. The obtained solid was slurried in water, filtered, rinsedwith water and dried under high vacuum to provide the title compound.

Example 248E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 248D for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.05 (s, 1H), 9.03(d, 1H), 8.44 (dd, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.67 (m, 1H), 7.65(d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.77 (dd, 1H), 6.53 (d, 1H), 6.49(dd, 1H), 4.55 (d, 2H), 3.80 (m, 4H), 3.08 (m, 4H), 2.77 (s, 2H), 2.26(t, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.88 (m, 4H), 1.39 (t, 2H), 0.94(s, 6H).

Example 250N-({5-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 250A5-chloro-6-((3-methyloxetan-3-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting(3-methyloxetan-3-yl)methanol for (tetrahydro-2H-pyran-4-yl)methanol andEXAMPLE 40A for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 250BN-({5-chloro-6-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 250A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.05 (s, 1H), 9.22(d, 1H), 8.51 (d, 1H), 8.42 (d, 1H), 8.09 (d, 1H), 7.66 (t, 2H),7.43-7.46 (m, 2H), 7.04-7.09 (m, 2H), 6.75 (dd, 1H), 6.45-6.54 (m, 2H),4.47 (s, 2H), 3.81-3.84 (m, 2H), 3.74 (d, 2H), 3.03-3.11 (m, 4H), 2.77(s, 2H), 2.26 (t, 2H), 2.10-2.17 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H),1.16 (s, 3H), 0.94 (s, 6H).

Example 2514-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 251A5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting(4-fluorotetrahydro-2H-pyran-4-yl)methanol for(tetrahydro-2H-pyran-4-yl)methanol and5-bromo-6-chloropyridine-3-sulfonamide for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 251B6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

To a suspension of5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide(200 mg) and cyclohexene (0.549 mL) in ethyl acetate (10 mL) was added10% palladium on carbon (57.6 mg). The suspension was stirred for 60minutes at 120° C. The reaction mixture was filtered and concentrated.The product was purified by reverse-phase flash chromatography (C18, 150g, 10%-100% acetonitrile/H₂O/trifluoroacetic acid 0.1%).

Example 251C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 251B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.06 (s, 1H), 9.29(d, 1H), 8.50 (dd, 1H), 8.41 (d, 1H), 8.07 (d, 1H), 7.66-7.70 (m, 1H),7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.84 (d, 1H), 6.75 (dd, 1H),6.52 (d, 1H), 6.49 (dd, 1H), 4.50 (d, 2H), 3.81-3.89 (m, 2H), 3.70-3.81(m, 2H), 3.02-3.12 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.10-2.18 (m,4H), 1.97 (s, 2H), 1.77-1.94 (m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2524-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 252A tert-butyl(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate

The title compound was prepared by substituting 1,3-difluoropropan-2-onefor 4′-chlorobiphenyl-2-carboxaldehyde and tert-butylmorpholin-2-ylmethylcarbamate for tert-butyl piperazine-1-carboxylate inEXAMPLE 1A.

Example 252B (4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methanamine

A solution of EXAMPLE 252A (538 mg) in dioxane (4 mL) was treated with4.0M HCl in dioxane solution (1.8 mL). The reaction was stirred at roomtemperature overnight. The reaction mixture was concentrated undervacuum and used without further purification.

Example 252C4-((4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 252B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 252D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(1,3-difluoropropan-2-yl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 252C for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.64 (s, 1H), 8.59 (t, 1H), 8.57 (d, 1H), 8.04(d, 1H), 7.83 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.07 (d, 1H), 7.03(d, 2H), 6.66 (dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 4.69 (t, 2H), 4.57(t, 2H), 3.85 (m, 1H), 3.70 (m, 1H), 3.52 (m, 2H), 3.41 (m, 2H), 3.07(br s, 4H), 2.91 (d, 1H), 2.74 (m, 3H), 2.59 (m, 1H), 2.43 (m, 1H), 2.20(m, 4H), 2.15 (m, 2H), 1.95 (br s, 2H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 253N-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 253A tert-butyl4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)piperidine-1-carboxylate

The title compound was prepared by substituting tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate fortetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 253B 5-chloro-6-(piperidin-4-ylmethoxy)pyridine-3-sulfonamideditrifluoroacetic acid

The title compound was prepared by substituting EXAMPLE 253A for EXAMPLE39A in EXAMPLE 39B.

Example 253C5-chloro-6-((1-(cyanomethyl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 253B (0.061 g), 2-chloroacetonitrile (0.017 g), sodium carbonate(0.025 g) and N,N-dimethylformamide (1 mL) were combined in a 4-mL vialand heated at 60° C. overnight. The cooled reaction mixture was dilutedwith ethyl acetate, washed with water and brine, dried (MgSO₄), filteredand concentrated. The concentrate was chromatographed on silica gel with2-10% methanol in CH₂Cl₂ as the eluent.

Example 253DN-[(5-chloro-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 253C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (400 MHz,pyridine-d₅) δ 13.04 (s, 1H), 9.14 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H),7.66 (t, 2H), 7.44 (m, 2H), 7.07 (m, 2H), 6.74 (dd, 1H), 6.50 (m, 2H),4.18 (d, 2H), 3.64 (s, 2H), 3.05 (s, 4H), 2.77 (m, 4H), 2.24 (m, 4H),2.13 (m, 4H), 1.97 (s, 2H), 1.69 (m, 3H), 1.41 (m, 4H), 0.93 (s, 6H).

Example 2544-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 254A (R)-tert-butyl3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate

The title compound was prepared by substituting (R)-tert-butyl3-aminopyrrolidine-1-carboxylate for 1-(tetrahydropyran-4-yl)methylaminein EXAMPLE 1F.

Example 254B (R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 254A for EXAMPLE113A in EXAMPLE 134A.

Example 254C(R)-4-(1-(2-(2-methoxyethoxy)ethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

To a solution of (R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesulfonamide(440 mg) in N,N-dimethylformamide (10 mL) was added sodium carbonate(132 mg) and 1-bromo-2-(2-methoxyethoxy)ethane (0.155 mL). The reactionmixture was heated at 60° C. for 18 hours and after an aqueous workup,the crude product was purified on silica gel with a 2.5-10% methanol inmethylene chloride gradient to provide the title compound.

Example 254D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yl-oxy)benzamide

The title compound was prepared by substituting EXAMPLE 254C for EXAMPLE130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine-d₅) δ 12.96 (m, 1H),9.25 (m, 1H), 8.57 (d, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.11 (d, 1H),7.66 (t, 1H) 7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.82 (d, 1H),6.76 (dd, 1H), 6.55 (m, 1H), 6.47 (m, 1H), 5.26 (br s, 1H), 4.02 (m,1H), 3.63 (m, 4H), 3.53 (m, 2H), 3.28 (s, 3H), 3.07 (m, 4H), 2.89-2.81(m, 2H), 2.78 (s, 2H), 2.75-2.66 (m, 3H), 2.37 (m, 1H), 2.26 (m, 2H),2.24-2.18 (m, 1H), 2.15 (m, 4H), 1.97 (s, 2H), 1.65 (m, 1H), 1.39 (t,2H), 0.94 (s, 6H).

Example 2554-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 255A(R)-4-(1-(2-(dimethylamino)acetyl)pyrrolidin-3-ylamino)-3-nitrobenzenesufonamide

The title compound was prepared by substituting 2-(dimethylamino)acetylchloride, hydrochloric acid for 1-bromo-2-(2-methoxyethoxy)ethane inEXAMPLE 254C except the reaction was stirred at ambient temperature for18 hours.

Example 255B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 255A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.01 (d, 1H),9.26 (m, 1H), 8.46-8.33 (m, 3H), 8.14 (d, 1H), 7.66 (m, 2H), 7.44 (d,2H), 7.07 (d, 2H), 7.01-6.89 (m, 1H), 6.76 (dd, 1H), 6.55 (m, 1H), 6.48(m, 1H), 5.32 (br s, 1H), 4.27-4.14 (m, 1H), 4.05-3.95 (m, 1H),3.82-3.62 (m, 3H), 3.27-3.15 (m, 2H), 3.07 (m, 4H), 2.77 (s, 2H), 2.34(2, 3H), 2.32 (s, 3H), 2.30-2.20 (m, 3H), 2.15 (m, 4H), 1.97 (s, 2H),1.87-1.81 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2564-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(oxetan-3-yl)azetidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 256A tert-butyl3-(2-nitro-4-sulfamoylphenylamino)azetidine-1-carboxylate

The title compound was prepared by substituting tert-butyl3-aminoazetidine-1-carboxylate for 4-methylpiperazin-1-aminedihydrochloride in EXAMPLE 6A.

Example 256B 4-(azetidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 256A for(S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate inEXAMPLE 168A.

Example 256C3-nitro-4-(1-(oxetan-3-yl)azetidin-3-ylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 256B fortert-butyl piperazine-1-carboxylate and 3-oxetanone for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 256D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(oxetan-3-yl)azetidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 256C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.04 (s, 1H), 9.27(d, 1H), 8.62 (d, 1H), 8.42 (d, 1H), 8.35 (dd, 1H), 8.09 (d, 1H), 7.67(m, 1H), 7.63 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.67(d, 1H), 6.55 (d, 1H), 6.48 (dd, 1H), 4.66 (t, 2H), 4.58 (m, 2H), 4.23(m, 1H), 3.71 (m, 3H), 3.12 (dd, 2H), 3.07 (m, 4H), 2.77 (s, 2H), 2.26(t, 2H), 2.14 (t, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 257N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 257A tert-butyl4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 126A for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 257B5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamideditrifluoroacetic acid

The title compound was prepared by substituting EXAMPLE 257A for EXAMPLE39A in EXAMPLE 39B.

Example 257C5-chloro-6-((1-(cyanomethyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 257B (0.166 g) in acetonitrile (3 mL) was treated with2-chloroacetonitrile (0.027 g) and sodium carbonate (0.064 g), heated at60° C. overnight, cooled to room temperature and chromatographed onsilica gel with 0 to 3% methanol in CH₂Cl₂ as the eluent. The obtainedsolid was slurried in water, filtered, rinsed with water and diethylether, and dried in a vacuum oven at 80° C.

Example 257DN-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 257C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (400 MHz,pyridine-d₅) δ 13.05 (s, 1H), 9.12 (d, 1H), 8.72 (d, 1H), 8.41 (d, 1H),8.10 (d, 1H), 7.66 (m, 2H), 7.44 (m, 2H), 7.07 (m, 2H), 6.75 (dd, 1H),6.50 (m, 2H), 4.49 (d, 2H), 3.72 (s, 2H), 3.06 (m, 4H), 2.77 (s, 2H),2.73 (m, 4H), 2.26 (t, 2H), 2.13 (m, 4H), 2.07 (m, 2H), 1.90 (m, 4H),1.39 (t, 2H), 0.93 (s, 6H).

Example 2584-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 258A (S)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate (1 g) in dichloromethane (50mL) was added triethylamine (1.604 mL) and 4-methylbenzene-1-sulfonylchloride (1.097 g). The mixture was stirred at ambient temperature undernitrogen for 72 hours. The reaction was diluted with methylene chloride(50 mL) and brine (100 mL). The brine layer was extracted with methylenechloride (75 mL). The combined organics were dried over sodium sulfate,filtered and concentrated. The crude material was purified on a silicagel column eluting with a 15-65% ethyl acetate in hexane gradient toprovide the title compound.

Example 258B (S)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate

A solution of EXAMPLE 258A (1.66 g) and sodium azide (0.581 g) inanhydrous N,N-dimethylformamide (10 mL) was stirred at 90° C. for 4hours. The mixture was cooled and concentrated to dryness. The residuewas taken up in 5% aqueous sodium carbonate solution and extracted withmethylene chloride. The organic solution was dried (MgSO₄), filtered andconcentrated to give a solid.

Example 258C (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate

This compound was obtained by hydrogenation of EXAMPLE 258B under 60 psiof hydrogen over 10% palladium on carbon in methanol for 24 hours,followed by filtration and evaporation of the solvent.

Example 258D (R)-tert-butyl2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 258C for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 258E (S)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 258D for EXAMPLE113A in EXAMPLE 134A.

Example 258F(R)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 258E for EXAMPLE134A and 2-(dimethylamino)acetyl chloride hydrochloride for methyliodide in EXAMPLE 134B.

Example 258G4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 258F for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.27 (d, 1H), 8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (dd, 1H), 6.75 (d, 1H),6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H), 4.20 (dd, 1H), 3.95-3.76 (m,2H), 3.60-3.40 (m, 3H), 3.32 (dd, 1H), 3.25-3.12 (m, 2H), 3.07 (m, 4H),2.80 (m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23 (s, 2H), 2.14 (m, 4H),1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2594-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 259A (R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate

The title compound was prepared by substituting (R)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate for (S)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate in EXAMPLE 258A.

Example 259B (R)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 259A for EXAMPLE258A in EXAMPLE 258B.

Example 259C (S)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 259B for EXAMPLE258B in EXAMPLE 258C.

Example 259D (S)-tert-butyl2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 259C for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 259E (R)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 259D for EXAMPLE113A in EXAMPLE 134A.

Example 259F(S)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 259E for EXAMPLE134A and 2-(dimethylamino)acetyl chloride hydrochloride for methyliodide in EXAMPLE 134B.

Example 259G4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 259F for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.27 (d, 1H), 8.87 (bs, 1H), 8.43 (d, 1H), 8.34 (dd, 1H), 8.10 (dd, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (dd, 1H), 6.75 (d, 1H),6.54 (s, 1H), 6.48 (s, 1H), 4.55 (dd, 1H), 4.20 (dd, 1H), 3.95-3.76 (m,2H), 3.60-3.40 (m, 3H), 3.32 (dd, 1H), 3.25-3.12 (m, 2H), 3.07 (m, 4H),2.80 (m, 1H), 2.77 (s, 2H), 2.26 (s, 6H), 2.23 (s, 2H), 2.14 (m, 4H),1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 260N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 260A5-chloro-6-((1-(2-(dimethylamino)acetyl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 253B (0.061 g), 2-(dimethylamino)acetyl chloride, hydrochloricacid (0.061 g), and sodium carbonate (0.032 g) were combined in a 4-mLvial with N,N-dimethylformamide (2 mL). The mixture was stirred atambient temperature for 3 days. Additional 2-(dimethylamino)acetylchloride, hydrochloric acid (0.037 g), sodium carbonate (0.032 g) andN,N-dimethylformamide (1 mL) were added and stirring was continued for24 hours. The reaction mixture was diluted with ethyl acetate, washedwith water and brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel with 0 to 20% methanol in CH₂Cl₂ as theeluent.

Example 260BN-[(5-chloro-6-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 260A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, pyridine-d₅) δ 12.91 (s, 1H), 9.16(d, 1H), 8.75 (d, 1H), 8.51 (d, 1H), 8.33 (d, 1H), 7.70 (d, 1H), 7.62(d, 1H), 7.45 (m, 2H), 7.09 (m, 2H), 6.77 (dd, 1H), 6.60 (d, 1H), 6.45(d, 1H), 4.81 (d, 1H), 4.15 (m, 3H), 3.24 (m, 2H), 3.04 (m, 4H), 2.89(m, 1H), 2.79 (s, 2H), 2.53 (m, 1H), 2.29 (m, 6H), 2.26 (m, 2H), 2.18(m, 4H), 1.98 (m, 2H), 1.91 (m, 1H), 1.71 (m, 2H), 1.39 (t, 2H), 1.25(m, 2H), 0.94 (s, 6H).

Example 261N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 261A (R)-tert-Butyl3-(3-chloro-5-sulfamoylpyridin-2-yloxy)pyrrolidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide and (R)-tert-butyl3-hydroxypyrrolidine-1-carboxylate for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 261B (R)-5-Chloro-6-(pyrrolidin-3-yloxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 261A fortert-butyl (4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate inEXAMPLE 252B.

Example 261C(R)-5-chloro-6-(1-(2,2-difluoroethyl)pyrrolidin-3-yloxy)pyridine-3-sulfonamide

A mixture of EXAMPLE 261B (353 mg), 1, 1-difluoro-2-iodoethane (268 mg),sodium carbonate (283 mg) in N,N-dimethylformamide (10 mL) was heated at80° C. overnight. The reaction mixture was cooled to room temperatureand diluted with ethyl acetate. The organic phase was washed with water,brine, dried over magnesium sulfate, filtered, and concentrated. Theresidue was loaded onto silica gel column and eluted using a gradient of0.5 to 3% methanol in dichloromethane to provide the title compound.

Example 261DN-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 261C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.55 (s,1H), 8.04 (s, 1H), 7.95 (d, 1H), 7.58 (d, 1H), 7.44 (t, 1H), 7.35 (m,3H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.33 (m, 1H), 6.24 (d, 1H), 6.25-5.97(m, 1H), 5.39 (m, 1H), 2.98 (m, 6H), 2.86 (m, 6H), 2.55 (m, 2H), 2.24(m, 7H), 1.96 (s, 2H), 1.83 (m, 1H), 1.39 (t, 2H), 0.93 (s, 6H)

Example 2624-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 262A(R)-4-(1-(cyanomethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesufonamide

The title compound was prepared by substituting 2-bromoacetonitrile for1-bromo-2-(2-methoxyethoxy)ethane in EXAMPLE 254C.

Example 262B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 262A for EXAMPLE130C in EXAMPLE 130D. 1H NMR (400 MHz, pyridine-d₅) δ 13.03 (s, 1H),9.27 (d, 1H), 8.53 (d, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.10 (d, 1H),7.67-7.64 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.81 (d, 1H), 6.76 (dd,1H), 6.54 (m, 1H), 6.48 (m, 1H), 5.15 (br s, 1H), 4.10 (m, 1H), 3.89 (s,2H), 3.07 (m, 4H), 2.93-2.86 (m, 2H), 2.80-2.77 (m, 3H), 2.61-2.53 (m,1H), 2.31-2.21 (m, 3H), 2.14 (m, 4H), 1.97 (s, 2H), 1.75-1.68 (m, 1H),1.39 (t, 2H), 0.94 (m, 6H).

Example 2634-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 263A tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate

Sodium hydride (6.63 g, 60% in mineral oil) was added totrimethylsulfoxonium iodide (36.5 g) in dimethyl sulfoxide (150 mL) andtetrahydrofuran (150 mL), was and stirred for 30 minutes. tert-Butyl4-oxopiperidine-1-carboxylate (25.4 g) was added and the reaction wasstirred for 3 hours. The reaction was poured into water (800 mL) andextracted three times with ether. The combined extracts were washedthree times with water, and brine, dried over Na₂SO₄, filtered, andconcentrated to yield the crude product which was used without furtherpurification.

Example 263B tert-butyl4-(2-(benzyloxy)benzyl)-4-hydroxypiperidine-1-carboxylate

(2-(Benzyloxy)phenyl)magnesium bromide (33.8 mL, 1M) was added to asolution of EXAMPLE 263A (6.0 g) and CuI (1.07 g) in tetrahydrofuran(220 mL) at 0° C. over 10 minutes. The reaction was quenched with pH 7buffer (20 mL), extracted twice with ether, and the combined extractswere washed with brine, dried over Na₂SO₄, filtered, and concentrated.The crude product was chromatographed on silica gel using 2-20% ethylacetate in hexanes to provide the title compound.

Example 263C tert-butyl4-hydroxy-4-(2-hydroxybenzyl)piperidine-1-carboxylate

EXAMPLE 263B (11.5 g) and methanol (120 mL) were added to Raney Nickel(1.150 g) in a 250 mL SS pressure bottle and stirred for 1 hour at 30psi under hydrogen. The mixture was filtered through a nylon membraneand the solution was concentrated to yield the title compound.

Example 263D tert-butyl4-hydroxy-4-(2-(trifluoromethylsulfonyloxy)benzyl)piperidine-1-carboxylate

A mixture of EXAMPLE 263C (4.6 g),N-phenylbis(trifluoromethanesulfonimide) (5.88 g), and Hunig's base(2.88 mL) in dichloromethane (100 mL) was stirred for 24 hours. Themixture was concentrated and chromatographed on silica gel using 5-50%ethyl acetate in hexanes to provide the title compound.

Example 263E tert-butyl4-((4′-chlorobiphenyl-2-yl)methyl)-4-hydroxypiperidine-1-carboxylate

A mixture of EXAMPLE 263D (4.3 g), 4-chlorophenylboronic acid (1.84 g),K₃PO₄ (2.91 g), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.36 g) in2-methyltetrahydrofuran (50 mL) was stirred at 70° C. for 24 hours. Thereaction was cooled and quenched with water (50 mL), extracted twicewith ether, and the combined extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude product waschromatographed on silica gel using 5-30% ethyl acetate in hexanes toprovide the title compound.

Example 263F tert-butyl4-((4′-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidine-1-carboxylate

Sodium hydride (0.36 g, 60% in mineral oil) was added to EXAMPLE 263E(4.3 g), in tetrahydrofuran (40 mL) and the reaction was stirred for 10minutes. Hexamethylphosphoramide (5 mL) and CH₃I (2.34 mL) were addedand the reaction was stirred at 50° C. for 18 hours. The reaction wascooled and quenched with water (50 mL), extracted twice with ether, andthe combined extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude product was chromatographed onsilica gel using 5-25% ethyl acetate in hexanes to provide the titlecompound.

Example 263G 4-((4′-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidine

The title compound was prepared by substituting EXAMPLE 263F for EXAMPLE1A in EXAMPLE 1B.

Example 263H methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidin-1-yl)benzoate

A solution of EXAMPLE 263G (1.4 g), EXAMPLE 3H (1.06 g) and Hunig's base(0.75 mL) in dimethylsulfoxide (20 mL) was stirred at 120° C. for 18hours. The reaction was cooled and quenched with water (200 mL),extracted three times with ether, and the combined extracts were washedthree times with water, and brine, dried over Na₂SO₄, filtered, andconcentrated. The crude product was chromatographed on silica gel using5-50% ethyl acetate in hexanes to provide the title compound.

Example 263I2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 263H for EXAMPLE3I in EXAMPLE 3J.

Example 263J4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 263I for EXAMPLE1E and EXAMPLE 96A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.71 (s, 1H), 11.58 (br s, 1H), 8.58 (d, 1H),8.28 (d, 1H), 8.05 (d, 1H), 7.56 (d, 1H), 7.52 (m, 1H), 7.46 (d, 1H),7.44 (d, 2H), 7.28 (m, 5H), 7.11 (dd, 1H), 6.62 (dd, 1H), 6.41 (dd, 1H),6.11 (d, 1H), 4.54 (d, 2H), 3.75 (m, 2H), 3.59 (m, 2H), 3.20 (m, 2H),2.97 (s, 3H), 2.81 (m, 2H), 2.74 (m, 2H), 1.89 (m, 2H), 1.83 (m, 2H),1.36 (m, 2H), 1.09 (m, 2H).

Example 2644-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-methoxypiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 263I for EXAMPLE1E in EXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.71 (s,1H), 11.40 (br s, 1H), 8.62 (t, 1H), 8.58 (d, 1H), 8.03 (d, 1H), 7.81(dd, 1H), 7.54 (m, 2H), 7.44 (m, 3H), 7.28 (m, 5H), 7.13 (dd, 1H), 6.62(dd, 1H), 6.41 (dd, 1H), 6.11 (d, 1H), 3.85 (dd, 2H), 3.31 (m, 4H), 3.20(m, 2H), 2.97 (s, 3H), 2.81 (m, 2H), 2.73 (m, 2H), 1.89 (m, 1H), 1.62(m, 2H), 1.38 (m, 2H), 1.25 (m, 2H), 1.09 (m, 2H).

Example 2654-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 265A benzyl 4-(piperidin-1-ylmethylene)piperidine-1-carboxylate

To a solution of benzyl 4-formylpiperidine-1-carboxylate (12.5 g) intoluene (120 mL) was added piperidine (6.46 g). The mixture was stirredat reflux under a Dean-Stark trap overnight. The mixture was thenconcentrated under vacuum and the residue was used directly in the nextstep.

Example 265B benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate

To a solution of EXAMPLE 265A (15.88 g) in ethanol (300 mL) was addedbut-3-enone (3.89 g). The mixture was stirred at reflux overnight. Thenacetic acid (30 mL) was added to the mixture which was stirred at refluxagain overnight. The mixture was then concentrated under vacuum and theresidue was diluted with ethyl acetate (400 mL) and washed with waterand brine and dried over Na₂SO₄. After filtration and evaporation of thesolvent, column purification gave the title compound.

Example 265C benzyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate

EXAMPLE 265B (21 g) and tetrahydrofuran (160 mL) were added to 5% Pt—Cwet (3.15 g) in a 250 mL pressure bottle and stirred for 1 hour at 30psi and room temperature.

The mixture was filtered through a nylon membrane and the filtrate wasconcentrated under vacuum to provide the title compound.

Example 265D benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of EXAMPLE 265C (8.0 g) in dichloromethane (200 mL) wasadded Dess-Martin Periodinane (11.2 g). The mixture was stirredovernight. The mixture was diluted with ethyl acetate (400 mL) andwashed with 2N aqueous NaOH, water, and brine. After drying over Na₂SO₄and filtration, concentration of the solvent gave the crude productwhich was used directly in the next reaction without furtherpurification.

Example 265E benzyl9-chloro-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate

Phosphorus oxychloride (2.33 mL) was added dropwise to a cooled (0° C.)solution of EXAMPLE 265D (7.5 g) in N,N-dimethylformamide (10 mL) anddichloromethane (30 mL). The mixture was then stirred overnight beforeit was diluted with ethyl acetate (300 mL) and washed with aqueoussodium acetate, water (3×), and brine and dried over Na₂SO₄. Afterfiltration and concentration, the crude product was used directly in thenext reaction without further purification.

Example 265F benzyl9-(4-chlorophenyl)-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate

To a mixture of 4-chlorophenylboronic acid (5.94 g), EXAMPLE 265E (11.01g), palladium(II) acetate (142 mg), K₂CO₃ (13.2 g) andtetrabutylammonium bromide (10.2 g) was added water (120 mL). Themixture was stirred at 50° C. overnight. The mixture was diluted withethyl acetate (400 mL) and washed with water (3×) and brine and driedover Na₂SO₄. After filtration and concentration, the residue was loadedon a column and eluted with 5 to 20% ethyl acetate in hexane to providethe title compound.

Example 265G benzyl8-((4-(3-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-9-(4-chlorophenyl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate

To a solution of EXAMPLE 15F (1.37 g) and EXAMPLE 265F (1.65 g) indichloromethane (20 mL) was added sodium triacetoxyborohydride (1.24 g).The mixture was stirred overnight. The mixture was diluted with ethylacetate (200 mL) and washed with 2N aqueous NaOH, water and brine. Afterdrying over Na₂SO₄, the mixture was filtered and the solvent wasevaporated under vacuum to provide the title compound.

Example 265H methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate

EXAMPLE 265G (2 g) and tetrahydrofuran (10 mL) were added to 20%Pd(OH)₂—C, wet (0.400 g) in a 50 mL pressure bottle and stirred for 16hours at 30 psi and room temperature. The mixture was filtered through anylon membrane and evaporation of the solvent gave the title compound.

Example 265I methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) wasadded 1, 3-difluoroacetone (139 mg) and sodium triacetoxyborohydride(157 mg). The mixture was stirred overnight. The mixture was dilutedwith ethyl acetate (200 mL) and washed with 2N aqueous NaOH, water andbrine. After drying over Na₂SO₄, the mixture was filtered and thesolvent was evaporated under vacuum to provide the title compound.

Example 265J2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 265I (320 mg) in tetrahydrofuran (4 mL) andmethanol (2 mL) was added LiOH H₂O (120 mg) and the solution was stirredovernight. The reaction was cooled, carefully neutralized with 1Naqueous HCl and extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with brine (25 mL), dried over sodiumsulfate, filtered and concentrated under vacuum to provide the titlecompound.

Example 265K4-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 265J for EXAMPLE1E in EXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.61 (s,1H), 8.49 (d, 2H), 7.72 (m, 1H), 7.49 (m, 2H), 7.32 (d, 2H), 7.07 (m,3H), 6.65 (dd, 1H), 6.35 (d, 1H), 6.20 (m, 1H), 4.66 (m, 2H), 4.50 (m,2H), 3.84 (m, 2H), 3.04 (m, 5H), 2.70 (m, 6H), 2.23 (m, 6H), 2.00 (m,4H), 1.35 (m, 12H).

Example 2664-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 266A methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) wasadded acetone (143 mg) and sodium triacetoxyborohydride (157 mg). Themixture was stirred overnight. The mixture was diluted with ethylacetate (200 mL) and washed with 2N aqueous NaOH, water and brine. Afterdrying over Na₂SO₄, the mixture was filtered and the solvent wasevaporated under vacuum to provide the title compound.

Example 266B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 266A for EXAMPLE265I in EXAMPLE 265J.

Example 266C4-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 266B for EXAMPLE1E in EXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.54 (s,1H), 8.38 (m, 2H), 7.93 (d, 1H), 7.60 (m, 3H), 7.39 (m, 4H), 7.09 (d,2H), 6.85 (d, 1H), 6.63 (dd, 1H), 6.27 (dd, 2H), 3.84 (m, 3H), 3.08 (m,8H), 2.71 (s, 3H), 2.15 (m, 8H), 1.71 (m, 9H), 1.24 (m, 11H)

Example 2674-(4-{[9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 265J for EXAMPLE1E and EXAMPLE 40B for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.56 (s, 1H), 8.38 (s, 1H), 8.06 (m, 1H), 7.57(d, 1H), 7.38 (m, 5H), 7.07 (m, 3H), 6.64 (dd, 1H), 6.33 (d, 1H), 6.23(m, 1H), 4.68 (d, 2H), 4.52 (d, 2H), 4.21 (d, 2H), 3.86 (dd, 2H), 3.08(m, 8H), 2.71 (m, 6H), 2.10 (m, 12H), 1.42 (m, 7H).

Example 2684-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 266B for EXAMPLE1E and EXAMPLE 40B for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.49 (s, 1H), 8.28 (d, 1H), 7.94 (dd, 2H), 7.60(d, 1H), 7.35 (m, 4 H), 7.08 (m, 2H), 6.61 (dd, 1H), 6.28 (dd, 2H), 4.18(d, 2H), 3.85 (m, 2H), 3.05 (m, 7H), 2.71 (s, 3H), 2.25 (m, 6H), 2.02(m, 2H), 1.63 (m, 8H), 1.30 (m, 9H).

Example 269N-({5-chloro-6-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 269A5-chloro-6-((4-fluoro-1-methylpiperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 257B (0.131 g) in N,N-dimethylformamide (3.0 mL) was treatedwith iodomethane (0.043 g) and sodium carbonate (0.079 g) and stirred atambient temperature for 3 days. The N,N-dimethylformamide was removed onhigh vacuum and the concentrate was chromatographed on aminefunctionalized silica gel with 0 to 2% methanol in CH₂Cl₂ as the eluent.

Example 269BN-({5-chloro-6-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 269A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, pyridine-d₅) δ 13.01 (s, 1H), 9.11(d, 1H), 8.71 (d, 1H), 8.44 (d, 1H), 8.16 (d, 1H), 7.66 (m, 2H), 7.44(m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.54 (d, 1H), 6.49 (dd, 1H), 4.49(d, 2H), 3.06 (m, 4H), 2.77 (s, 2H), 2.68 (m, 2H), 2.38 (m, 2H), 2.26(m, 5H), 2.14 (t, 4H), 1.97 (m, 6H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 270N-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 270A5-chloro-6-((1-(2-(dimethylamino)acetyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 257B (0.131 g), 2-(dimethylamino)acetyl chloride, hydrochloricacid (0.139 g), and sodium carbonate (0.048 g) were combined in a 5-mLvial with N,N-dimethylformamide (3.0 mL) and stirred overnight atambient temperature. Additional sodium carbonate (0.048 g) was addedfollowed by 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139g) and stirring was continued over a second night. The reaction mixturewas concentrated under high vacuum, slurried in CH₂Cl₂, filtered,concentrated and chromatographed on amine functionalized silica gel with0 to 4% methanol in CH₂Cl₂ as the eluent.

Example 270BN-[(5-chloro-6-{[1-(N,N-dimethylglycyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 270A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.04 (s, 1H), 9.12(d, 1H), 8.73 (d, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.44(m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.52 (d, 1H), 6.49 (dd, 1H), 4.66(d, 1H), 4.52 (dd, 2H), 4.07 (d, 1H), 3.46 (m, 1H), 3.40 (m, 1H), 3.30(m, 1H), 3.11 (m, 1H), 3.06 (m, 4H), 2.77 (s, 2H), 2.35 (s, 6H), 2.26(t, 2H), 2.14 (m, 4H), 2.05 (m, 2H), 1.97 (s, 2H), 1.81 (m, 2H), 1.39(t, 2H), 0.93 (s, 6H).

Example 2714-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 271A tert-butyl4-((4′-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidine-1-carboxylate

A solution of EXAMPLE 263E (2.0 g) and diethylaminosulfur trifluoride(1.39 mL) in dichloromethane (40 mL) was stirred for 24 hours. Thereaction was quenched with water (30 mL), extracted twice with ether,and the combined extracts were washed with water, and brine, dried overNa₂SO₄, filtered, and concentrated. The crude product waschromatographed on silica gel using 5% ethyl acetate in hexanes toprovide the title compound.

Example 271B 4-((4′-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidine

The title compound was prepared by substituting EXAMPLE 271A for EXAMPLE1A in EXAMPLE 1B.

Example 271C methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 271B for EXAMPLE263G in EXAMPLE 263H.

Example 271D2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 271C for EXAMPLE3I in EXAMPLE 3J.

Example 271E4-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 271D for EXAMPLE1E EXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.66 (s, 1H),11.46 (br s, 1H), 8.62 (t, 1H), 8.56 (d, 1H), 8.03 (d, 1H), 7.81 (dd,1H), 7.52 (m, 3H), 7.44 (d, 2H), 7.28 (m, 5H), 7.14 (m, 1H), 6.68 (dd,1H), 6.40 (dd, 1H), 6.19 (d, 1H), 3.84 (dd, 2H), 3.31 (m, 9H), 2.95 (d,2H), 2.81 (m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.45 (m, 2H), 1.29 (m,2H).

Example 2724-{4-[(4′-chlorobiphenyl-2-yl)methyl]-4-fluoropiperidin-1-yl}-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 271D for EXAMPLE1E and EXAMPLE 96A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 11.64 (br s, 1H), 8.58 (m, 1H),8.25 (m, 1H), 8.03 (d, 1H), 7.70 (dd, 1H), 7.50 (m, 4H), 7.43 (m, 3H),7.28 (m, 4H), 7.15 (m, 1H), 6.68 (dd, 1H), 6.40 (dd, 1H), 6.19 (d, 1H),4.54 (d, 2H), 4.04 (m, 1H), 3.75 (m, 2H), 3.58 (m, 2H), 2.95 (d, 2H),2.80 (m, 2H), 1.88 (m, 2H), 1.82 (m, 2H), 1.48 (m, 2H), 1.28 (m, 2H),0.85 (m, 2H).

Example 2734-(4-{[9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 266B for EXAMPLE1E and EXAMPLE 42A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.57 (s, 1H), 7.97 (d, 1H), 7.77 (s, 1H), 7.55(m, 2H), 7.45 (m, 1H), 7.36 (m, 3H), 7.08 (d, 2H), 6.62 (dd, 2H), 6.35(dd, 1H), 6.21 (d, 1H), 3.82 (m, 3H), 3.06 (m, 9H), 2.72 (m, 3H), 2.25(m, 8H), 2.09 (m, 2H), 1.56 (m, 9H), 1.20 (m, 10H).

Example 274N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 274A(R)-5-chloro-6-(1-(3-fluoro-2-(fluoromethyl)propyl)pyrrolidin-3-yloxy)pyridine-3-sulfonamide

The title compound was prepared by substituting 1,3-difluoropropan-2-onefor 4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 261B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 274BN-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 274A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.52 (s,1H), 8.32 (d, 1H), 8.01 (d, 1H), 7.93 (d, 1H), 7.59 (d, 1H), 7.42 (m,1H), 7.33 (m, 3H), 7.05 (d, 2H), 6.63 (dd, 1H), 6.31 (dd, 1H), 6.25 (d,1H), 5.38 (m, 1H), 4.65 (t, 2H), 4.53 (t, 2H), 3.02 (s, 4H), 2.94 (m,5H), 2.75 (s, 2H), 2.66 (m, 1H), 2.23 (m, 7H), 1.96 (s, 2H), 1.82 (m,1H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 2754-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 275A 3-(2-(benzyloxy)ethoxy)tetrahydrofuran

Tetrahydrofuran-3-ol (0.881 g) in tetrahydrofuran (15 mL) was treatedwith 60% sodium hydride (0.8 g). After 10 minutes,((2-bromoethoxy)methyl)benzene (3.23 g) was added. The solution wasstirred for 16 hours. The reaction mixture was partitioned between waterand ethyl acetate. The aqueous layer was separated, and was extractedwith additional ethyl acetate twice. The combined organic layers werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel eluting with1:1 ethyl acetate:hexane to provide the title compound.

Example 275B 2-(tetrahydrofuran-3-yloxy)ethanol

EXAMPLE 275A (0.85 g) and 5% palladium on carbon (0.1 g) in ethanol (10mL) was treated with a balloon of hydrogen. The reaction was stirredovernight. The solid was filtered off, and the filtrate was concentratedto give the title compound.

Example 275C3-nitro-4-(2-(tetrahydrofuran-3-yloxy)ethoxy)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 275B for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 275D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[2-(tetrahydrofuran-3-yloxy)ethoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 275C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.65 (s,1H), 8.32 (s, 1H), 8.00-8.02 (m, 2H), 7.49-7.52 (m, 2H), 7.39-7.41 (m,1H), 7.38 (d, 2H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.21 (d,1H), 4.33-4.35 (m, 2H), 4.18-4.21 (m, 1H), 3.62-3.67 (m, 4H), 3.09 (s,4H), 2.83 (s, 2H), 2.26 (s, 2H), 2.15 (s, 2H), 1.96 (s, 2H), 1.85-1.94(m, 2H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 2764-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 276A trans-4-(aminomethyl)cyclohexanecarbonitrile

To a solution of tert-butyl(trans-4-(cyanomethyl)cyclohexyl)methylcarbamate (500 mg) indichloromethane (10 mL) was slowly added trifluoroacetic acid (2 mL) at0° C. The reaction mixture was warmed to room temperature, stirred for 1hour and concentrated to provide the title compound.

Example 276B4-((trans-4-cyanocyclohexyl)methylamino)-3-nitrobenzenesulfonamide

A mixture of 4-fluoro-3-nitrobenzenesulfonamide (347 mg) and EXAMPLE276A (300 mg) in tetrahydrofuran (20 mL) was treated with triethylamine(1.4 mL) overnight and concentrated. The residue was triturated withethyl acetate to provide the title compound.

Example 276C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 276B in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.36 (s, 1H), 8.60 (t, 1H), 8.56(d, 1H), 8.04 (d, 1H), 7.79 (dd, 1H), 7.47-7.54 (m, 3H), 7.34 (d, 2H),7.01-7.09 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.25 (t,2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.57-2.68 (m, 1H), 2.17 (d, 6H),1.92-2.06 (m, 4H), 1.78 (d, 2H), 1.66 (s, 1H), 1.35-1.53 (m, 4H),0.96-1.10 (m, 2H), 0.92 (s, 6H).

Example 277N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 277A methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoromethanesulfonic anhydride (40 mL) was added. Thereaction mixture was warmed to room temperature and stirred for 24hours. The organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated to give the product.

Example 277B methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 277A (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether (4×200 mL) was added and the mixturewas filtered. The combined ether solution was concentrated to give theproduct.

Example 277C (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 277B (53.8 g) and ether (400 mL),was added methanol (25 mL) slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted withether (3×100 mL). The extracts were dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with0-30% ethyl acetate/hexanes.

Example 277D tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 277C (29.3 g)and triethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C., and the mixturewas stirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was addedand the mixture was stirred at room temperature for 24 hours. Thesuspension was washed with brine, dried, (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with10-20% ethyl acetate/hexanes.

Example 277E1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

EXAMPLE 277D (1 g) was stirred in dichloromethane (10 mL),trifluoroacetic acid (10 mL), and triethylsilane (1 mL) for 1 hour. Themixture was concentrated, taken up in a mixture of dichloromethane (100mL) and saturated aqueous Na₂CO₃ solution (20 mL) and stirred for 10minutes. The layers were separated, and the organic layer was dried overNa₂SO₄, filtered, and concentrated to give the product.

Example 277F 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) intetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide intetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl(triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirredat room temperature for 24 hours. The reaction was diluted with ether,and the resulting solution was washed twice with water. The extractswere dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 10% ethyl acetate/hexanes.

Example 277G 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

To a mixture of EXAMPLE 277F (24.3 g) in tetrahydrofuran (500 mL) at−78° C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate(11.5 mL) was added, and the mixture was allowed to warm to roomtemperature over 1 hour. The reaction was poured into water, extractedthree times with ethyl acetate, and the combined extracts were washedwith brine and concentrated. The crude product was taken up intetrahydrofuran (200 mL) at 0° C., and 1M NaOH (69 mL) was added,followed by 30% H₂O₂ (8.43 mL), and the solution was stirred for 1 hour.Na₂S₂O₃ (10 g) was added, and the pH was adjusted to 4-5 withconcentrated HCl and solid NaH₂PO₄. The solution was extracted twicewith ethyl acetate, and the combined extracts were washed with brine,dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 5-25% ethyl acetate/hexanes.

Example 277H methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate

A mixture of EXAMPLE 277G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The crude product waschromatographed on silica gel with 2-50% ethyl acetate/hexanes.

Example 277I methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of EXAMPLE 277H (1.55 g), EXAMPLE 277E (2.42 g), and HK₂PO₄(1.42 g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24hours. The reaction was cooled, diluted with ether (400 mL), and washedthree times with 1M NaOH, and brine, and concentrated. The crude productwas chromatographed on silica gel with 10-50% ethyl acetate/hexanes.

Example 277J2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 277I (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50° C.was stirred for 24 hours. The reaction was cooled, added to NaH₂PO₄solution, and extracted three times with ethyl acetate. The combinedextracts were washed with brine, and concentrated to give the pureproduct.

Example 277K 5,6-dichloropyridine-3-sulfonamide

To a solution of 5,6-dichloropyridine-3-sulfonyl chloride (32.16 g) inisopropyl alcohol (300 mL) at 0° C. was added a 30% aqueous solution ofNH₄OH (50.8 mL). After stirring overnight, the solvent was reduced to ⅓of the original volume. It was then partitioned between water and ethylacetate. The aqueous layer was extracted with additional ethyl acetate.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was chromatographed on silicagel. The material was then slurried in 1:9 ethyl acetate/hexanes,filtered and dried under vacuum to give the title compound.

Example 277L tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g) intetrahydrofuran (5 mL) was treated with 1.0 N LiAlH₄ in tetrahydrofuran(2.54 mL) at 0° C. The reaction mixture was stirred at room temperaturefor 2 hours. Water (0.6 mL) was added to the reaction mixture drop-wise,followed by 2 N aqueous NaOH (0.2 mL). The reaction was stirred foranother 1 hour. The solid was removed by filtration via a pack ofdiatomaceous earth and washed with ethyl acetate. The filtrate waswashed with brine, dried over MgSO₄, filtered, and concentrated to givethe product.

Example 277M tert-butyl4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperidine-1-carboxylate

To a solution of EXAMPLE 277L (1 g) in tetrahydrofurab (15 mL) was addedNaH (60% dispersion in mineral oil, 685 mg), and the solution wasstirred for 10 minutes. EXAMPLE 227K (1 g) was added and the reactionstirred for 24 hours. The mixture was poured into water, neutralizedwith 10% HCl, and extracted with ethyl acetate three times. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified with flash column chromatographyon silica gel eluting with 30% ethyl acetate in hexanes.

Example 277N5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamideditrifluoroacetic acid

EXAMPLE 277M (13 mL) was treated with trifluoroacetic acid (2.363 mL),stirred at ambient temperature for 2 hours, concentrated and dried togive the title compound.

Example 27705-chloro-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 277N (0.088 g) and oxetan-3-one (0.014 g) were combined indichloromethane (2.0 mL) and dimethylformamide (1.0 mL) and stirred atambient temperature for 45 minutes. Sodium triacetoxyborohydride (0.064g) was added in portions. Stirring was continued overnight at ambienttemperature. Additional oxetan-3-one (0.014 g) was added and stirringwas continued for 30 minutes at ambient temperature before more sodiumtriacetoxyborohydride (0.064 g) was added. The reaction mixture wasstirred for 72 hours at ambient temperature, concentrated,chromatographed on silica gel with 0 to 5% methanol in dichloromethaneas the eluent, and dried in a vacuum oven at 80° C. to give the titlecompound.

Example 277PN-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 277J (0.063 g), EXAMPLE 277O (0.042 g),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.032g), and 4-dimethylaminopyridine (0.027 g) were combined in a 4-mL vialwith dichloromethane (1.0 mL) and stirred overnight at ambienttemperature. The reaction mixture was chromatographed directly withoutaqueous workup on silica gel with 0-4% methanol in dichloromethane asthe eluent. Fractions containing the desired product were concentrated,slurried in acetonitrile, concentrated and dried overnight in a vacuumoven at 80° C. to give the title compound. ¹H NMR (500 MHz, pyridine-d₅)δ 13.05 (s, 1H), 9.13 (d, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H),7.67 (m, 1H), 7.66 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H),6.51 (m, 2H), 4.63 (m, 4H), 4.53 (d, 2H), 3.39 (m, 1H), 3.07 (m, 4H),2.77 (s, 2H), 2.51 (m, 2H), 2.25 (m, 2H), 2.18 (m, 2H), 2.13 (m, 4H),2.06 (t, 2H), 1.97 (s, 2H), 1.89 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 2784-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 278A5-bromo-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting2-(tetrahydro-2H-pyran-4-yl)ethanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 36B.

Example 278B5-cyano-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 278A for EXAMPLE36B in EXAMPLE 36C.

Example 278C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 278B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.60 (s,1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.96 (d, 1H), 7.56 (d, 1H), 7.45-7.47(m, 1H), 7.40 (s, 1H), 7.36 (d, 2H), 7.06 (d, 2H), 6.67 (dd, 1H), 6.34(dd, 1H), 6.25 (d, 1H), 4.47 (d, 2H), 3.80-3.84 (m, 2H), 3.24-3.28 (m,2H), 3.12 (s, 2H), 2.16 (s, 2H), 1.97 (s, 2H), 1.61-1.71 (m, 4H), 1.40(t, 2H), 1.21-1.25 (m, 2H), 0.93 (s, 6H).

Example 2794-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(3-furylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 279A 4-(furan-3-ylmethoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting furan-3-ylmethanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 279B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(3-furylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 279A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.69 (s,1H), 8.34 (s, 1H), 8.03-8.06 (m, 2H), 7.83 (s, 1H), 7.69 (t, 1H),7.51-7.53 (m, 4H), 7.34-7.36 (m, 2H), 7.04-7.06 (m, 2H), 6.68 (dd, 1H),6.57 (s, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 5.23 (s, 2H), 3.10 (s, 4H),2.83 (s, 2H), 2.15-2.32 (m, 6H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 280N-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 280A (R)-tert-butyl3-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide and (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 280B(R)-5-chloro-6-(pyrrolidin-3-ylmethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 280A fortert-butyl (4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate inEXAMPLE 252B.

Example 280C(R)-5-chloro-6-((1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting 1,3-difluoropropan-2-onefor 4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 280B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 280DN-[(5-chloro-6-{[(3R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 280C for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.57 (s,1H), 8.38 (d, 1H), 8.07 (d, 1H), 7.96 (d, 1H), 7.57 (d, 1H), 7.44 (m,1H), 7.35 (m, 3H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.33 (dd, 1H), 6.23 (d,1H), 4.65 (d, 2H), 4.53 (dd, 2H), 2.92 (m, 8H), 2.75 (m, 4H), 2.58 (m,2H), 2.20 (m, 6H), 1.96 (m, 4H), 1.53 (m, 1H), 1.39 (t, 2H), 0.89 (s,6H).

Example 281N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 281A(R)-5-chloro-6-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 280B for EXAMPLE261B in EXAMPLE 261C.

Example 281BN-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 281A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.59 (s,1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.56 (d, 1H), 7.46 (m,1H), 7.41 (d, 1H), 7.34 (d, 2H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.35 (dd,1H), 6.23 (m, 1H), 6.03 (m, 1H), 3.06 (s, 4H), 2.84 (m, 6H), 2.63 (m,4H), 2.20 (m, 6H), 1.94 (m, 3H), 1.53 (m, 1H), 1.39 (t, 2H), 0.91 (s,6H).

Example 282N-[(5-chloro-6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 282A5-chloro-6-((1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 257B (0.088 g) and 1,3-difluoropropan-2-one (0.028 g) werecombined in dichloromethane (2 mL) and N,N-dimethylformamide (0.500 mL)and stirred at ambient temperature for 45 minutes. Sodiumtriacetoxyborohydride (0.064 g) was added in portions and then thereaction mixture was stirred overnight at ambient temperature.Additional 1,3-difluoropropan-2-one (0.028 g) was added, followed 30minutes later by the addition of more sodium triacetoxyborohydride(0.064 g). The reaction mixture was stirred at ambient temperature for72 hours. Additional 1,3-difluoropropan-2-one (0.028 g) was again added,followed 30 minutes later by the addition of more sodiumtriacetoxyborohydride (0.064 g). The reaction mixture was stirredovernight at ambient temperature. Additional 1,3-difluoropropan-2-one(0.028 g) was again added, followed 30 minutes later by the addition ofmore sodium triacetoxyborohydride (0.064 g). The reaction mixture wasstirred overnight at ambient temperature. The reaction mixture wasconcentrated under high vacuum to remove N,N-dimethylformamide and thenchromatographed on silica gel with 0 to 4% methanol in CH₂Cl₂ as theeluent.

Example 282BN-[(5-chloro-6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 282A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, pyridine-d₅) δ 13.05 (s, 1H), 9.12(t, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.44(m, 2H), 7.07 (m, 2H), 6.75 (dd, 1H), 6.50 (m, 2H), 4.77 (dd, 1H), 4.65(dd, 1H), 4.52 (dd, 2H), 3.06 (m, 4H), 2.93 (t, 1H), 2.80 (m, 5H), 2.52(m, 1H), 2.26 (t, 2H), 2.13 (m, 4H), 2.04 (m, 2H), 1.97 (s, 2H), 1.85(m, 2H), 1.39 (t, 2H), 1.28 (m, 2H), 0.93 (s, 6H).

Example 283N-({3-chloro-4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 283A3-chloro-4-((4-fluoro-1-methylpiperidin-4-yl)methoxy)benzenesulfonamide

To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol (0.265 g) intetrahydrofuran (2 mL) was added sodium hydride (0.288 g). After 15minutes, 3-chloro-4-fluorobenzenesulfonamide (0.377 g) was added as asolution in tetrahydrofuran (1 mL). The reaction was stirred for 2hours, quenched with water (5 mL), adjusted to pH-7 with 1N aqueous HCl,and extracted with dichloromethane (2×25 mL). The organic layer waswashed with brine (25 mL), dried over magnesium sulfate, filtered andconcentrated. Silica gel chromatography (Reveleris 40 g) eluting with agradient of 0.1% to 10% methanol containing 2N NH₃/dichloromethane over30 minutes gave the title compound.

Example 283BN-({3-chloro-4-[(4-fluoro-1-methylpiperidin-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 283A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.60 (s, 1H), 10.68-9.84 (m, 1H), 7.99 (d, 1H),7.79 (d, 1H), 7.63 (t, 1H), 7.54 (d, 1H), 7.50-7.38 (m, 2H), 7.34 (d,2H), 7.04 (d, 3H), 6.64 (dd, 1H), 6.36 (dd, 1H), 6.22 (s, 1H), 4.23 (d,2H), 3.03 (s, 6H), 2.71 (m, 4H), 2.07 (m, 12H), 1.38 (s, 3H), 1.24 (s,2H), 0.92 (s, 6H).

Example 2844-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 284A3-cyano-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

To a solution of (tetrahydro-2H-pyran-4-yl)methanol (0.258 g) intetrahydrofuran (5 mL) was added sodium hydride (0.355 g) and thereaction stirred at room temperature for 15 minutes. EXAMPLE 52A (0.400g) was added and the reaction stirred for an additional 1 hour. Thereaction was poured into ethyl acetate (50 mL) and 1N aqueous HCl (35mL). The organic layer was washed with brine (35 mL) dried overmagnesium sulfate, filtered, and concentrated. Silica gel chromatography(Reveleris 40 g) eluting with a gradient of 10% to 100% ethylacetate/hexanes over 30 minutes gave the title compound.

Example 284B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-cyano-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 284A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.60-11.16 (m, 1H), 8.15 (s,1H), 8.08-8.01 (m, 2H), 7.58-7.46 (m, 3H), 7.35 (d, J=8.4, 2H), 7.29 (d,1H), 7.04 (d, 2H), 6.68 (d, 1H), 6.40 (dd, 1H), 6.20 (s, 1H), 4.05 (d,2H), 3.89 (d, 2H), 3.37 (d, 4H), 3.09 (s, 4H), 2.81 (s, 2H), 2.21 (d,7H), 1.96 (s, 2H), 1.67 (d, 2H), 1.39 (s, 2H), 0.92 (s, 6H).

Example 285N-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 285A5-chloro-6-((1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 257B (0.263 g), 1,1-difluoro-2-iodoethane (0.23 g), and sodiumcarbonate (0.254 g) were combined in a 20-mL vial withN,N-dimethylformamide (6 ml) and stirred at 70° C. overnight. Thereaction mixture was concentrated under high vacuum and thenchromatographed on silica gel with 0 to 5% methanol in CH₂Cl₂ as theeluent.

Example 285BN-[(5-chloro-6-{[1-(2,2-difluoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 285A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, pyridine-d₅) δ 13.05 (s, 1H), 9.12(d, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.43(m, 2H), 7.06 (m, 2H), 6.75 (dd, 1H), 6.50 (m, 2H), 6.18 (tt, 2H), 4.51(d, 2H), 3.07 (m, 4H), 2.80 (m, 6H), 2.60 (td, 2H), 2.25 (t, 2H), 2.13(m, 4H), 2.03 (t, 2H), 1.97 (s, 2H), 1.93 (m, 1H), 1.85 (m, 1H), 1.39(t, 2H), 0.93 (s, 6H).

Example 286N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 286A3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 37C for(4-fluoro-1-methylpiperidin-4-yl)methanol in EXAMPLE 283A.

Example 286BN-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 286A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.71 (s, 1H), 11.56-11.16 (m, 1H), 8.06 (d,1H), 7.90 (d, 1H), 7.81 (d, 1H), 7.64-7.45 (m, 3H), 7.34 (d, 2H), 7.26(d, 1H), 7.04 (d, 2H), 6.68 (d, 1H), 6.42 (dd, 1H), 6.18 (s, 1H), 4.28(d, 2H), 3.78 (d, 2H), 3.61 (dd, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.17(d, 6H), 1.87 (dd, 6H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 287N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 287A (4,4-difluorocyclohexyl)methanol

Ethyl 4,4-difluorocyclohexanecarboxylate (1.0 g, 5.20 mmol) in diethylether (2 mL) was added dropwise to lithium aluminium hydride (0.24 g) indiethyl ether (15 mL), and heated under reflux for 4 hours. The reactionwas then cooled to 0° C., and water was added (0.24 mL), followed by 5Naqueous NaOH (0.24 mL) and water (0.72 mL). Then Na₂SO₄ and more diethylether (40 mL) were added, and the mixture was stirred for 30 minutes,then filtered through celite. After concentration, the residue wasdiluted with CH₂Cl₂ and Na₂SO₄ was added, and the mixture was filteredand concentrated to provide the title compound.

Example 287B5-chloro-6-((4,4-difluorocyclohexyl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 287A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 287CN-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 287B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.63 (s,1H), 8.46 (d, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.56 (d, 1H), 7.47 (m,2H), 7.35 (d, 2H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.37 (m, 1H), 6.21 (d,1H), 4.25 (d, 2H), 3.07 (br m, 4H), 2.82 (br s, 2H), 2.30 (br m, 4H),2.16 (br m, 2H), 2.00, 1.95, 1.85 (all m, total 9H), 1.40 (t, 2H), 1.37(m, 2H), 0.92 (s, 6H).

Example 2884-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 288A 5-Nitro-3-(trifluoromethyl)pyridin-2-ol

3-(Trifluoromethyl)pyridin-2-ol (2.3 g) was added to concentratedsulfuric acid (15 mL) at 0° C. The mixture was stirred at 0° C. for 5minutes. To this solution was added fuming nitric acid (6 mL) dropwiseover 5 minutes. The reaction mixture was stirred at room temperature for2 hours, and then heated at 50° C. for 3 hours. After cooling, thereaction mixture was poured onto ice (200 g), and the mixture wasextracted with ethyl acetate three times. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentratedunder reduced pressure to provide the title compound.

Example 288B 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

A mixture of EXAMPLE 288A (1.69 g), phosphorus pentachloride (2.03 g),and phosphoryl trichloride (0.97 mL) was heated at 90° C. for 3 hours.After cooling, the reaction mixture was poured into ice, and extractedwith ethyl acetate three times. The extract was washed with brine, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica geleluting with 10% ethyl acetate in hexanes to provide the title compound.

Example 288C 6-Chloro-5-(trifluoromethyl)pyridin-3-amine

A mixture of iron (1.5 g) and ammonium chloride (2.38 g) in water (40mL) was stirred at room temperature for 5 minutes. To this suspensionwas added EXAMPLE 288B in methanol (40 mL). The reaction mixture wasstirred at room temperature for 1 hour. More iron (1.8 g) was added tothe reaction mixture, and it was stirred for another 3 hours. The solidfrom the reaction mixture was filtered off, and the filtrate waspartitioned between water and ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with 20% ethyl acetate in hexanesto provide the title compound.

Example 288D 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride

Under ice-cooling, thionyl chloride (4 mL) was added dropwise over 20minutes to water (27 mL). The mixture was stirred overnight for 12 hoursto give a SO₂ containing solution. Separately, EXAMPLE 288C (1.14 g) indioxane (5 mL) was added to concentrated HCl (20 mL) at 0° C. Thesolution was stirred for 5 minutes. To this suspension/solution wasadded sodium nitrite (0.44 g) in water (6 mL) dropwise at 0° C. Thesolution was stirred at 0° C. for 3 hours. During this time, any solidformed was crushed with a glass rod to make sure that EXAMPLE 288C wascompletely reacted. To the SO₂ containing solution was added copper(I)chloride (0.115 g). Then, to this solution was added the diazotizedEXAMPLE 288C at 0° C. The solution was stirred for 30 minutes. Thereaction mixture was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with 5% ethyl acetate inhexanes to provide the title compound.

Example 288E 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonamide

EXAMPLE 288D (2.03 g) in dioxane (20 mL) solution was cooled to 0° C.Ammonium hydroxide solution was added dropwise. The reaction mixture wasstirred at 0° C. for 2 hours followed by room temperature overnight. Thesolvent was partially removed, and the residue was partitioned betweenwater and ethyl acetate. The organic phase was washed with brine, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica geleluting with 0-3% methanol in dichloromethane to afford the titlecompound.

Example 288F tert-butyl4-fluoro-4-((5-sulfamoyl-3-(trifluoromethyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 288E for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 322A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 288G6-((4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 288F fortert-butyl (4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate inEXAMPLE 252B.

Example 288H6-((1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

The title compound was prepared by substituting 1,3-difluoropropan-2-onefor 4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 288G for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 28814-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-{[1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 288H for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.50 (s,1H), 8.57 (s, 1H), 8.27 (d, 1H), 7.91 (d, 1H), 7.58 (d, 1H), 7.40 (m,1H), 7.35 (d, 2H), 7.28 (d, 1H), 7.05 (d, 2H), 6.61 (dd, 1H), 6.29 (dd,1H), 6.24 (d, 1H), 4.67 (d, 2H), 4.55 (d, 2H), 4.50 (s, 1H), 4.44 (s,1H), 3.06 (m, 5H), 2.73 (m, 6H), 2.19 (d, 6H), 1.90 (m, 7H), 1.39 (t,2H), 0.93 (s, 6H).

Example 2894-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-chloro-6-[2-(tetrahydrofuran-2-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 289A5-chloro-6-(2-(tetrahydrofuran-2-yl)ethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting2-(tetrahydro-2H-pyran-4-yl)ethanol for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for EXAMPLE 36A inEXAMPLE 36B.

Example 289B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-chloro-6-[2-(tetrahydrofuran-2-yl)ethoxy]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 289A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.66 (s,1H), 8.52 (d, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.50-7.55 (m, 3H), 7.35(d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.38 (dd, 1H), 6.21 (d, 1H),4.39-4.51 (m, 4H), 3.87-3.94 (m, 1H), 3.73-3.78 (m, 1H), 3.57-3.62 (m,1H), 3.11 (s, 4H), 2.89 (s, 2H), 2.33 (s, 4H), 2.15 (s, 2H), 1.77-2.01(m, 7H), 1.45-1.54 (m, 1H), 1.40 (t, 2H), 0.93 (s, 6H).

Example 2904-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-methylpiperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 290A 2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde

Into a 250 ml round-bottomed flask was added N,N-dimethylformamide (3.5mL) in dichloromethane (30 mL). The mixture was cooled to −10° C., andphosphoryl trichloride (4 mL) was added dropwise. The solution waswarmed up to room temperature and 3,3-dimethylcyclohexanone (5.5 mL) wasadded slowly. The mixture was heated to reflux overnight. The reactionmixture was quenched by 0° C. solution of sodium acetate (25 g in 50 mLwater). The aqueous layer was extracted with ether (3×200 mL). Theorganic layers were combined, dried over Na₂SO₄, filtered, and driedunder vacuum.

Example 290B 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde

Into a 1 L round-bottomed flask was added EXAMPLE 290A (6.8 g),4-chlorophenylboronic acid (6.5 g) and palladium(II) acetate (0.2 g) inwater (100 mL) to give a suspension. Potassium carbonate (15 g) andtetrabutylammonium bromide (10 g) were added. After degassing aftersubjecting to vacuum and nitrogen, the mixture was stirred at 45° C. for4 hours. After filtering through silica gel, diethyl ether (4×200 mL)was used to extract the product. The combined organic layers were driedover Na₂SO₄ and filtered. The filtrate was concentrated and purified byflash chromatography on silica with 0-10% ethyl acetate in hexanes toprovide the title compound.

Example 290C tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-3-methylpiperazine-1-carboxylate

To a solution of tert-butyl 3-methylpiperazine-1-carboxylate (0.256 g)and EXAMPLE 290B (0.350 g) in dichloromethane (2 mL) was added sodiumtriacetoxyborohydride (0.406 g) and the reaction was stirred at roomtemperature overnight. The reaction was quenched with NaHCO₃ solution(50 mL) and extracted with dichloromethane (50 mL). The organic layerwas dried over magnesium sulfate, filtered and concentrated. Silica gelchromatography (Reveleris 40 g) eluting with a gradient of 0.5% to 2.5%methanol/dichloromethane gave the title compound.

Example 290D1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-2-methylpiperazine

A solution of EXAMPLE 290C (0.298 g) and HCl (4.0M in dioxane, 2 mL)were stirred for 1 hour. The reaction was concentrated and partitionedbetween dichloromethane (100 mL) and NaHCO₃ (100 mL). The organic layerwas washed with brine (50 mL), dried over magnesium sulfate, filteredand concentrated to provide the title compound.

Example 290E methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-3-methylpiperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 290D for EXAMPLE3E in EXAMPLE 3I.

Example 290F2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-3-methylpiperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 290E for EXAMPLE15G in EXAMPLE 15H.

Example 290G4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-methylpiperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 290F for EXAMPLE1E in EXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.66 (s,1H), 11.54-11.30 (m, 1H), 8.62-8.53 (m, 2H), 8.03 (d, 1H), 7.78 (d, 1H),7.48 (d, 3H), 7.34 (d, 2H), 7.06 (t, 3H), 6.68 (d, 1H), 6.38 (dd, 1H),6.21 (s, 1H), 3.84 (d, 2H), 3.23 (s, 4H), 2.75 (s, 4H), 1.64 (s, 8H),1.62 (d, 2H), 1.42-1.17 (m, 6H), 0.92 (s, 6H), 0.87 (s, 3H).

Example 2914-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(cyclopropylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 291A tert-butyl 2-cyanoethyl(cyclopropyl)carbamate

To a solution of 3-(cyclopropylamino)propanenitrile (5.0 g) intetrahydrofuran (30 mL) was added di-tert-butyl dicarbonate (9.91 g) anda catalytic amount of 4-dimethylaminopyridine. The mixture was stirredovernight. The mixture was diluted with ethyl acetate (400 mL) andwashed with 5% aqueous HCl, water and brine. After drying over Na₂SO₄,the mixture was filtered, and the solvent was evaporated under vacuum toprovide the title compound.

Example 291B tert-butyl 3-aminopropyl(cyclopropyl)carbamate

EXAMPLE 291A (9.75 g) and 7M NH₃-methanol (25 mL) were added to a Ra—Ni2800, water slurry (19.50 g, 332 mmol) in a 250 mL pressure bottle andstirred for 2 hours at 30 psi and room temperature. The mixture wasfiltered through a nylon membrane and evaporation of the solvent gavethe title compound.

Example 291C tert-butylcyclopropyl(3-(2-nitro-4-sulfamoylphenylamino)propyl)carbamate

To a solution of 4-chloro-3-nitrobenzenesulfonamide (2.5 g), and EXAMPLE291B (2.26 g) in dioxane (20 mL) was added N,N-diisopropylethylamine (5mL). The mixture was stirred at reflux overnight. The mixture wasdiluted with ethyl acetate (400 mL) and washed with water and brine.After drying over Na₂SO₄, the mixture was filtered, and the solvent wasevaporated under vacuum to provide the title compound.

Example 291D tert-butyl3-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)propyl(cyclopropyl)carbamate

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 291C for EXAMPLE 1F in EXAMPLE 1G.

Example 291E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(cyclopropylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a solution of EXAMPLE 291D (2.56 g) in dichloromethane (10 mL) wasadded trifluoroacetic acid (10 mL). The mixture was stirred for 2 hours.The mixture was concentrated under vacuum and the residue was dissolvedin dichloromethane (300 mL) and washed with aqueous NaHCO₃, water, andbrine and dried over Na₂SO₄. Filtration and evaporation of the solventgave the crude product. The title compound was obtained by dissolving200 mg of the crude material in dimethylsulfoxide/methanol (1:1, 10 mL)and loaded on Gilson, C18(100A) 250×121.2 mm (10 micron), eluting with30% acetonitrile to 65% acetonitrile over 40 minutes. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.54 (s, 1 H), 8.43 (m, 2H), 7.94 (d, 1H), 7.71(dd, 1H), 7.57 (d, 1H), 7.43 (m, 1H), 7.34 (m, 3H), 7.05 (d, 2H), 6.90(d, 1H), 6.63 (dd, 1H), 6.29 (d, 2H), 3.43 (m, 2H), 2.96 (m, 6H), 2.73(m, 2H), 2.22 (m, 7H), 1.87 (m, 4H), 1.38 (m, 3H), 0.94 (m, 6H), 0.62(m, 4H).

Example 292N-{[5-chloro-6-(2-methoxyethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 292A 5-chloro-6-(2-methoxyethoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide and 2-methoxyethanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 292BN-{[5-chloro-6-(2-methoxyethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 292A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.63 (s,1H), 8.48 (d, 1H), 8.17 (d, 1H), 8.01 (d, 1H), 7.56 (d, 1H), 7.49 (m,2H), 7.35 (d, 2H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.37 (m, 1H), 6.21 (d,1H), 4.52 (m, 2H), 3.70 (m, 2H), 3.28 (s, 3H), 3.13 (br m, 4H), 2.88 (brs, 2H), 2.34 (br m, 4H), 2.16 (br m, 2H), 1.97 (s, 2H), 1.40 (t, 2H),0.92 (s, 6H).

Example 2934-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 293A

The title compound was prepared by substituting5-bromo-2,3-difluoropyridine for 4-fluoro-3-nitrobenzenesulfonamide inEXAMPLE 24A.

Example 293B tert-butyl5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-ylcarbamate

The title compound was prepared by substituting EXAMPLE 293A for EXAMPLE248A in EXAMPLE 248B.

Example 293C5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonylchloride

The title compound was prepared by substituting EXAMPLE 293B for EXAMPLE248B in EXAMPLE 248C.

Example 293D5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 293C for EXAMPLE248C in EXAMPLE 248D.

Example 293E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 293D for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, pyridine-d₅) δ 13.07 (s, 1H), 9.05(d, 1H), 8.44 (dd, 1H), 8.41 (d, 1H), 8.09 (d, 1H), 7.67 (t, 1H), 7.65(d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.53 (d, 1H), 6.49(dd, 1H), 4.21 (d, 2H), 3.96 (dd, 2H), 3.31 (td, 2H), 3.07 (m, 4H), 2.77(s, 2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (m, 3H), 1.58 (dd, 2H), 1.38(m, 4H), 0.94 (s, 6H).

Example 294N-[(3-chloro-4-{[1-(methoxyacetyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 294A tert-butyl4-((2-chloro-4-sulfamoylphenoxy)methyl)piperidine-1-carboxylate

The title compound was prepared by substitutingtert-butyl-4-(hydroxymethyl)piperidine-1-carboxylate for(4-fluoro-1-methylpiperidin-4-yl)methanol in EXAMPLE 283A.

Example 294B tert-butyl4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-chlorophenoxy)methyl)piperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 294A for EXAMPLE 1F in EXAMPLE 1G.

Example 294C2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(3-chloro-4-(piperidin-4-ylmethoxy)phenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

To EXAMPLE 294B (0.286 g) in dichloromethane (3 mL) was addedtrifluoroacetic acid (1 mL) and the reaction stirred at roomtemperature. After 3 hours the reaction was concentrated to provide thetitle compound.

Example 294DN-[(3-chloro-4-{[1-(methoxyacetyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To EXAMPLE 294C (0.75 g) as a solution in dichloromethane (1 mL) wasadded N,N-diisopropylethylamine (0.055 mL) followed by 2-methoxyacetylchloride (6 μl). After stirring for 10 minutes the reaction was loadedonto silica gel (Reveleris 40 g) and eluted using a gradient of 0.5% to3.5% methanol/dichloromethane over 30 minutes (flow=40 mL/minutes) toprovide the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.71 (s, 1H), 11.55-11.24 (m, 1H), 8.06 (d, 1H), 7.88 (d, 1H), 7.78 (d,1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.48 (d, 1H), 7.34 (d, 2H), 7.21 (d,1H), 7.04 (d, 2H), 6.67 (d, 1H), 6.42 (dd, 1H), 6.18 (s, 1H), 4.42-4.32(m, 1H), 4.03 (dd, 4H), 3.86-3.74 (m, 1H), 3.28 (s, 3H), 3.07 (s, 5H),2.77 (s, 3H), 2.30-1.92 (m, 9H), 1.77 (s, 2H), 1.31 (d, 4H), 0.92 (s,6H).

Example 295N-[(3-chloro-4-{[1-(N,N-dimethylglycyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting 2-(dimethylamino)acetylchloride for 2-methoxyacetyl chloride in EXAMPLE 294D. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.58 (s, 1H), 10.35-9.94 (m, 1H), 7.96 (d, 1H),7.74 (d, 1H), 7.55 (d, 2H), 7.45 (s, 1H), 7.41-7.29 (m, 3H), 7.05 (d,3H), 6.63 (d, 1H), 6.37-6.32 (m, 1H), 6.22 (d, 1H), 4.39 (d, 1H), 3.94(s, 6H), 3.01 (s, 6H), 2.73 (m, 4H), 2.55 (m, 5H), 2.19 (s, 6H), 1.95(m, 2H), 1.82 (m, 2H), 1.38 (s, 4H), 0.93 (s, 6H).

Example 2964-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 296A tert-butyl4-((4,4-dimethyl-2-oxocyclohexyl)methyl)piperidine-1-carboxylate

3,3-Dimethylcyclohexanone (5.60 mL) was added to sodiumbis(trimethylsilyl)amide (45.3 mL, 1M in tetrahydrofuran), and thereaction was stirred for 1 hour. tert-Butyl4-(bromomethyl)piperidine-1-carboxylate (11.1 g) in dimethylsulfoxide(30 mL) was added, and the reaction was stirred at 50° C. for 24 hours.The reaction was cooled, poured into water (300 mL), extracted threetimes with ether, and the combined extracts were washed three times withwater, and brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude product was chromatographed on silica gel using 5-20% ethylacetate in hexanes to provide the title compound.

Example 296B tert-butyl4-((2-(4-chlorophenyl)-2-hydroxy-4,4-dimethylcyclohexyl)methyl)piperidine-1-carboxylate

(4-Chlorophenyl)magnesium bromide (14.1 mL, 1M in ether) was added toEXAMPLE 296A (3.25 g) in tetrahydrofuran (40 mL) at −78° C., and thereaction was stirred for 20 minutes, and then allowed to warm to roomtemperature overnight. The reaction was quenched with pH 7 buffer (20mL), extracted with 2× ether, and the combined extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The crude productwas chromatographed on silica gel using 1-20% ethyl acetate in hexanesto provide the title compound.

Example 296Ctrans-4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl)methyl)piperidine

The title compound was prepared by substituting EXAMPLE 296B for EXAMPLE1A in EXAMPLE 1B.

Example 296D Trans-methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl)methyl)piperidin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 296C for EXAMPLE263G in EXAMPLE 263H.

Example 296ETrans-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexyl)methyl)piperidin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 296D for EXAMPLE3I in EXAMPLE 3J.

Example 296FTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 296E for EXAMPLE1E in EXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.69 (s,1H), 11.36 (br s, 1H), 8.60 (t, 1H), 8.55 (d, 1H), 8.03 (d, 1H), 7.78(dd, 1H), 7.52 (m, 3H), 7.27 (d, 2H), 7.16 (d, 2H), 7.09 (m, 1H), 6.63(dd, 1H), 6.38 (dd, 1H), 6.11 (d, 1H), 3.83 (dd, 2H), 3.52 (m, 2H), 3.26(m, 4H), 2.61 (m, 2H), 2.35 (m, 1H), 1.89 (m, 2H), 1.76 (m, 1H), 1.62(m, 2H), 1.38 (m, 4H), 1.25 (m, 6H), 1.12 (m, 2H), 0.95 (m, 2H), 0.94(s, 3H), 0.88 (s, 3H).

Example 2974-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamideExample 297A6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 288E for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 297B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 297A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.49 (s,1H), 8.56 (d, 1H), 8.23 (d, 1H), 7.90 (d, 1H), 7.58 (d, 1H), 7.40 (m,1H), 7.34 (m, 2H), 7.26 (d, 1H), 7.05 (d, 2H), 6.61 (dd, 1H), 6.28 (dd,1H), 6.24 (d, 1H), 4.24 (d, 2H), 3.86 (dd, 2H), 3.30 (m, 4H), 3.00 (s,4H), 2.73 (s, 2H), 2.16 (m, 6H), 1.97 (m, 2H), 1.61 (dd, 2H), 1.33 (m,4H), 0.93 (s, 6H).

Example 298N-({5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 298A6-((trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-5-chloropyridine-3-sulfonamide

The title compound was prepared by substituting(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for EXAMPLE 36A inEXAMPLE 36B.

Example 298BN-({5-chloro-6-[(trans-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 298A for EXAMPLE11B in EXAMPLE 11D. After the reaction was over, the solvent wasremoved, and the residue was treated with 1:1 trifluoroaceticacid/dichloromethane for two hours. The solvents were removed, and theresidue was purified by reverse phase Gilson Prep HPLC system with aPhenomenex prep column (Luna, 5μ, C18(2), 250×21.20 mm, 5 Å) elutingwith 20-80% acetonitrle in water with 0.1% trifluoroacetic acid toprovide the title compound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ11.65 (s, 1H), 8.47 (s, 1H), 8.15 (s, 1H), 8.01 (d, 1H), 7.54 (d, 1H),7.48-7.49 (m, 1H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.37 (d,1H), 6.21 (s, 1H), 4.53 (t, 1H), 4.18 (d, 2H), 3.08 (s, 4H), 2.84 (s,2H), 2.29 (s, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.79-1.83 (m, 5H), 1.39(t, 2H), 1.08-1.13 (m, 5H), 0.93 (s, 6H).

Example 2994-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 299A3-cyano-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 37C for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 284A.

Example 299B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 299A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.72 (s, 1H), 10.24-9.27 (m, 1H), 8.21 (d, 1H),8.12 (dd, 1H), 8.05 (d, 1H), 7.63-7.46 (m, 3H), 7.45-7.31 (m, 3H), 7.07(d, 2H), 6.70 (dd, 1H), 6.42 (s, 1H), 6.23 (s, 1H), 4.38 (d, 2H),3.91-3.73 (m, 2H), 3.68-3.51 (m, 2H), 3.22-2.96 (m, 10H), 2.31-2.12 (m,2H), 1.99 (s, 6H), 1.43 (t, 2H), 0.93 (s, 6H).

Example 3004-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(trans-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 300A6-((trans-4-methoxycyclohexyl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 288E for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 121A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 300B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(trans-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 300A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.50 (s,1H), 8.56 (d, 1H), 8.23 (d, 1H), 7.90 (d, 1H), 7.58 (d, 1H), 7.40 (m,1H), 7.35 (d, 2H), 7.27 (d, 1H), 7.05 (d, 2H), 6.61 (dd, 1H), 6.28 (dd,1H), 6.24 (d, 1H), 4.20 (d, 2H), 3.23 (s, 3H), 3.03 (m, 5H), 2.73 (s,2H), 2.18 (m, 6H), 1.98 (m, 5H), 1.80 (m, 3H), 1.39 (t, 2H), 1.09 (m,4H), 0.93 (s, 6H).

Example 3014-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(cis-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 301A6-((cis-4-methoxycyclohexyl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 288E for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 121A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 301B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({6-[(cis-4-methoxycyclohexyl)methoxy]-5-(trifluoromethyl)pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 301A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.49 (m,1H), 8.54 (m, 1H), 8.23 (d, 1H), 7.91 (d, 1H), 7.59 (d, 1H), 7.40 (m,1H), 7.34 (m, 2H), 7.27 (d, 1H), 7.04 (d, 2H), 6.61 (dd, 1H), 6.29 (dd,1H), 6.24 (d, 1H), 4.20 (d, 2H), 3.37 (m, 2H), 3.19 (s, 3H), 3.00 (s,4H), 2.73 (s, 2H), 2.18 (m, 6H), 1.96 (s, 2H), 1.80 (m, 3H), 1.50 (dd,2H), 1.37 (m, 6H), 0.93 (s, 6H).

Example 302N-({5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 302A4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperidine

EXAMPLE 296B (1.0 g) was stirred in dichloromethane (15 mL) andtrifluoroacetic acid (15 mL) at 35° C. for 48 hours. The mixture wasconcentrated, taken up in dichloromethane (100 mL), and stirred, andsaturated Na₂CO₃ solution (20 mL) was added slowly. The solution wasseparated and the organic layer was dried over Na₂SO₄, filtered, andconcentrated to provide the title compound.

Example 302B methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperidin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 302A for EXAMPLE263G in EXAMPLE 263H.

Example 302C2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperidin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 302B for EXAMPLE3I in EXAMPLE 3J.

Example 302D 1,1-difluoro4-methylenecyclohexane

Butyllithium (12.32 mL, 2.5 M solution in hexanes) was added to asolution of methyltriphenylphosphonium chloride (9.63 g) intetrahydrofuran (50 mL) at 0° C., and the reaction was stirred for 5minutes. 4,4-Difluorocycleohexanone (3.76 g) in dioxane (150 mL) wasthen added, and the reaction was stirred for 30 minutes. Water (3 mL)was added, and then hexane (150 mL) was slowly added, the reaction wasfiltered, and the solution carried on.

Example 302E 4,4-difluoro-1-(hydroxymethyl)cyclohexanol

To the solution from EXAMPLE 302D was added water (75 mL), thenN-methylmorpholine-N-oxide (6.4 mL, 50% solution in water) and OsO₄(14.2 g, 2.5 wt % solution in tert-butanol) were added, and the reactionwas stirred for 96 hours at 50° C. The solution was cooled to roomtemperature, treated with saturated aqueous Na₂S₂O₃ solution (100 mL)for 30 minutes, and then acidified with concentrated aqueous HCl. Thesolution was then extracted three times with ethyl acetate, and theorganic layers were combined, washed with 1M HCl, and brine, andconcentrated. The crude mixture was chromatographed on silica gel using10-100% ethyl acetate in hexanes, and then 5% methanol in ethyl acetateto give the product.

Example 302F5-chloro-6-((4,4-difluoro-1-hydroxycyclohexyl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 302E fortetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 302GN-({5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 302C for EXAMPLE1E and EXAMPLE 302F for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (br s, 2H), 8.51 (s, 1H), 8.18 (s, 1H),8.02 (d, 1H), 7.53 (m, 3H), 7.35 (d, 2H), 7.04 (d, 2H), 6.69 (dd, 1H),6.39 (dd, 1H), 6.21 (d, 1H), 4.88 (s, 1H), 4.27 (s, 2H), 3.10 (m, 4H),2.88 (m, 1H), 2.33 (m, 2H), 2.15 (m, 4H), 1.97 (s, 2H), 1.91 (m, 2H),1.73 (m, 4H), 1.52 (m, 1H), 1.40 (m, 2H), 1.31 (m, 1H), 0.93 (s, 3H),0.91 (m, 2H).

Example 303N-[(3-chloro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 303A trans-4-morpholinocyclohexyl)methanol

To tert-butyl trans-4-(hydroxymethyl)cyclohexylcarbamate (0.500 g) wasadded hydrogen chloride (4.0M in dioxane, 2.2 mL) and the reaction wasstirred for 1 hour and concentrated. The resulting solid was dissolvedin acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (1.523mL) followed by 1-bromo-2-(2-bromoethoxy)ethane (0.556 g) and heated to60° C. After stirring overnight the reaction was concentrated, loadedonto silica gel (Reveleris 40 g) and eluted using a gradient of 1% to10% methanol/dichloromethane over 30 minutes (flow=40 mL/min) to providethe title compound.

Example 303B3-chloro-4-(((1r,4r)-4-morpholinocyclohexyl)methoxy)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 303A for(4-fluoro-1-methylpiperidin-4-yl)methanol in EXAMPLE 283A.

Example 303CN-[(3-chloro-4-{[trans-4-(morpholin-4-yl)cyclohexyl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 303B for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 10.96-10.59 (m, 1H), 8.02 (d,1H), 7.82 (d, 1H), 7.69 (s, 1H), 7.50 (dd, 3H), 7.38-7.30 (m, 2H),7.15-6.99 (m, 3H), 6.65 (dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 3.91 (d,2H), 3.64 (s, 4H), 3.04 (s, 4H), 2.73 (s, 7H), 2.18 (s, 6H), 1.93 (m,6H), 1.80-1.65 (m, 1H), 1.32 (m, 6H), 0.92 (s, 6H).

Example 3044-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(1,3-thiazol-5-ylmethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a solution of EXAMPLE 291E (95 mg) in dichloromethane (2 mL) andacetic acid (0.5 mL) was added thiazole-5-carbaldehyde (13 mg) followedby sodium triacetoxyborohydride (35 mg). The mixture was stirredovernight. The mixture was diluted with dichloromethane (300 mL) andwashed with aqueous NaHCO₃, water, and brine and dried over Na₂SO₄.Filtration and evaporation of the solvent gave crude product which wasdissolved in dimethylsulfoxide/methanol (6 mL, 1:1) and loaded onGilson, C18(100A) 250×121.2 mm (10 micron), with 30% acetonitrile to 65%acetonitrile over 40 minutes. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.67 (s, 1H), 8.95 (s, 1H), 8.57 (m, 2H), 8.03 (d, 1H), 7.78 (m, 2H),7.49 (m, 3H), 7.35 (m, 2H), 7.02 (m, 3H), 6.67 (dd, 1H), 6.38 (dd, 1H),6.19 (d, 1H), 4.00 (s, 2H), 3.05 (d, 4H), 2.73 (m, 2H), 2.60 (m, 2H),2.18 (m, 7H), 1.95 (s, 2H), 1.79 (m, 3H), 1.37 (m, 3H), 0.92 (s, 6H),0.45 (m, 4H).

Example 305N-({3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 305A3-chloro-4-((trans-4-hydroxycyclohexyl)methoxy)benzenesulfonamide

(Trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol (275 mg,prepared according to a procedures in WO 2008/124878) and3-chloro-4-fluorobenzenesulfonamide (259 mg) in tetrahydrofuran (15 mL)were treated with sodium hydride (180 mg, 60%) overnight. The reactionwas quenched with water (1 mL) and trifluoroacetic acid (4 mL) wasadded. The resulting mixture was stirred for 1 hour and concentrated.The residue was triturated with water and methanol to provide the titlecompound.

Example 305BN-({3-chloro-4-[(trans-4-hydroxycyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 305A in place of EXAMPLE 11B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.71 (s, 1H), 11.38 (s, 1H), 8.06 (d, 1H), 7.87(d, 1H), 7.76 (dd, 1H), 7.57 (d, 1H), 7.51-7.55 (m, 1H), 7.49 (d, 1H),7.34 (d, 2H), 7.18 (d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.42 (dd, 1H),6.18 (d, 1H), 4.54 (d, 1H), 3.91 (d, 2H), 3.07 (s, 4H), 2.75 (s, 2H),2.17 (d, 6H), 1.95 (s, 2H), 1.78-1.90 (m, 4H), 1.63-1.75 (m, 1H), 1.38(t, 2H), 1.00-1.25 (m, 4H), 0.92 (s, 6H).

Example 3064-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-chloro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 306A3-chloro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting4-fluoro-3-chlorobenzenesulfonamide for4-chloro-3-nitrobenzenesulfonamide,(tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-aminedihydrochloride and Hunig's base forN¹,N¹,N²,N²-tetramethylethane-1,2-diamine in EXAMPLE 6A.

Example 306B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-chloro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 306A for EXAMPLE11B in EXAMPLE 11D. 1H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.80 (s,1H), 11.17 (br s, 1H), 8.09 (d, 1H), 7.71 (d, 1H), 7.63 (d, 1H), 7.58(dd, 1H), 7.53 (dd, 1H), 7.50 (d, 1H), 7.34 (d, 2H), 7.03 (d, 2H), 6.74(d, 1H), 6.66 (dd, 1H), 6.42 (m, 1H), 6.40 (t, 1H), 6.16 (d, 1H), 3.83(m, 2H), 3.24 (m, 2H), 3.10 (m, 2H), 3.06 (br m, 4H), 2.72 (s, 2H), 2.17(br m, 6H), 1.95 (s, 2H), 1.83 (m, 1H), 1.59 (br m, 2H), 1.38 (t, 2H),1.20 (ddd, 2H), 0.92 (s, 6H).

Example 3074-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl)phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 307A4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-(trifluoromethyl)benzenesulfonamide

The title compound was prepared by substituting4-fluoro-3-(trifluoromethyl)benzenesulfonamide for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 37C for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 307B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl)phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 307A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (400 MHz,pyridine-d₅) δ 13.07 (s, 1H), 8.78 (d, 1H), 8.58 (dd, 1H), 8.42 (d, 1H),8.09 (d, 1H), 7.67 (t, 1H), 7.65 (d, 1H), 7.43 (m, 2H), 7.16 (d, 1H),7.06 (m, 2H), 6.74 (dd, 1H), 6.51 (m, 2H), 4.21 (d, 2H), 3.87 (m, 2H),3.78 (td, 2H), 3.06 (m, 4H), 2.76 (s, 2H), 2.25 (t, 2H), 2.13 (m, 4H),1.95 (m, 6H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 3084-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 308A4-(3-(cyclopropylamino)propylamino)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 291C (4.14 g) in dichloromethane (10 mL) wasadded trifluoroacetic acid (10 mL). The mixture was stirred for 2 hours.The mixture was concentrated under vacuum and the residue was dissolvedin dichloromethane (300 mL) and washed with aqueous NaHCO₃, water, andbrine and dried over Na₂SO₄. Filtration and evaporation of solvent gavethe title compound.

Example 308B4-(3-(cyclopropyl(2,2,2-trifluoroethyl)amino)propylamino)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 308A (314 mg) in dichloromethane (6 mL) wasadded 2,2,2-trifluoroethyl trifluoromethanesulfonate (255 mg) andN,N-diisopropylethylamine (258 mg). The mixture was stirred overnight.The mixture was diluted with dichloromethane (300 mL) and washed withaqueous NaHCO₃, water, brine and dried over Na₂SO₄. Filtration andevaporation of solvent gave the title compound.

Example 308C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(2,2,2-trifluoroethyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 308B for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.38 (m, 1H), 8.55 (d, 2H), 8.03(d, 1H), 7.81 (dd, 1H), 7.50 (m, 3H), 7.34 (d, 2H), 7.05 (m, 3H), 6.67(dd, 1H), 6.38 (dd, 1H), 6.19 (d, 1H), 3.07 (m, 4H), 2.82 (m, 4H), 2.18(m, 7H), 1.38 (m, 2H), 0.92 (s, 6H), 0.44 (m, 4H).

Example 309N-[(3-chloro-4-{[1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a solution of EXAMPLE 294B (0.150 g) in dichloromethane (2 mL) wasadded trifluoroacetic acid (1 mL). After stirring for 1 hour thereaction was concentrated and dried under high vacuum. The residue wasdissolved in dichloromethane (2 mL) and treated with sodiumtriacetoxyborohydride (0.050 g) and oxetan-3-one (0.017 g) and stirredovernight at room temperature. The reaction was quenched with saturatedaqueous NaHCO₃ (20 mL) and extracted into dichloromethane (50 mL). Theorganic layer was separated, washed with brine (25 mL), dried overNa₂SO₄, filtered, and concentrated. Silica gel chromatography (Reveleris40 g) eluting with a gradient of 0.5% to 5% methanol/dichloromethaneover 30 minutes (flow=40 mL/min) provided the title compound. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ 11.70 (s, 1H), 11.21 (s, 1H), 8.05 (d,1H), 7.87 (d1H), 7.75 (dd, 1H), 7.61-7.42 (m, 3H), 7.42-7.26 (m, 2H),7.18 (d, 1H), 7.14-6.97 (m, 2H), 6.67 (dd, 1H), 6.41 (dd, 1H), 6.18 (d,1H), 4.51 (dt, 4H), 3.99 (d, 2H), 3.56-3.32 (m, 1H), 3.06 (s, 4H),2.89-2.68 (m, 4H), 2.16 (d, 6H), 2.01-1.69 (m, 7H), 1.50-1.07 (m, 4H),0.92 (s, 6H).

Example 3104-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,5-difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 310A3,5-difluoro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

EXAMPLE 37C (0.423 g) in tetrahydrofuran (30 mL) was treated with NaH(60% oil dispersion) (0.480 g), stirred 20 minutes at ambienttemperature, treated with 3,4,5-trifluorobenzenesulfonamide (0.633 g)and stirred 30 minutes. N,N-Dimethylacetamide (15 mL) was added toincrease solubility of the reactants and stirring was continuedovernight at ambient temperature. Additional NaH (60% oil dispersion)(0.480 g) and N,N-dimethylacetamide (15 mL) were added and the mixturewas heated overnight at 50° C. The reaction was quenched with saturatedaqueous NH₄Cl solution and then partitioned between saturated aqueousNH₄Cl solution and ethyl acetate. The organic layer was washed withwater and brine, dried (MgSO₄), filtered and concentrated. Theconcentrate was chromatographed on amine functionalized silica gel with0 to 2% methanol in CH₂Cl₂ as the eluent. The residue was furtherpurified by reverse phase HPLC on a C18 column using a gradient of10-70% acetonitrile/0.1% trifluoroacetic acid in water to provide thetitle compound.

Example 310B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,5-difluoro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 310A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz,pyridine-d₅) δ 13.06 (s, 1H), 8.41 (d, 1H), 8.11 (m, 2H), 8.08 (d, 1H),7.66 (m, 2H), 7.44 (m, 2H), 7.07 (m, 2H), 6.75 (dd, 1H), 6.52 (d, 1H),6.50 (dd, 1H), 4.26 (d, 2H), 3.85 (dd, 1H), 3.83 (dd, 1H), 3.74 (m, 2H),3.07 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (s, 2H),1.87 (m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 3114-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 311A4-(3-(cyclopropyl(oxetan-3-yl)amino)propylamino)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 308A (314 mg) in dichloromethane (5 mL) wasadded oxetan-3-one (72 mg) followed by sodium triacetoxyborohydride (318mg). The mixture was stirred overnight. The mixture was diluted withdichloromethane (300 mL) and washed with aqueous NaHCO₃, water and brineand dried over Na₂SO₄. After filtration, evaporation of the solvent gavethe crude title compound.

Example 311B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclopropyl(oxetan-3-yl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 311A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 11.37 (s, 1H), 8.68 (s, 1H), 8.54(d, 1H), 8.02 (d, 1H), 7.79 (d, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.03(m, 3H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.19 (d, 1H), 4.62 (m, 2H), 4.48(t, 2H), 3.98 (m, 1H), 3.37 (m, 2H), 3.06 (m, 4H), 2.73 (d, 2H), 2.59(m, 2H), 2.23 (m, 6H), 1.95 (s, 2H), 1.74 (m, 3H), 1.38 (t, 2H), 0.92(s, 6H), 0.41 (m, 4H).

Example 312N-[(3-chloro-4-{[1-(1-methyl-L-prolyl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To EXAMPLE 294B (0.065 g) was added hydrogen chloride (4.0M in dioxane,0.339 mL) and a few drops of methanol. After 30 minutes, the reactionwas concentrated, and (S)-1-methylpyrrolidine-2-carboxylic acid (0.013g), N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (0.026 g), suspended in dichloromethane (0.5 mL) wereadded followed by diisopropylethylamine (0.036 mL). The mixture stirredat room temperature. After stirring overnight, the reaction mixture wasloaded onto silica gel (Reveleris 40 g) and eluted using a gradient of1% to 10% methanol (containing 1N NH₃)/dichloromethane over 30 minutes(flow=40 mL/minutes) to provide the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.51 (s, 1H), 10.00-9.22 (m, 1H), 7.92 (d, 1H),7.68 (d, 1H), 7.57 (d, 1H), 7.47 (dd, 1H), 7.44-7.38 (m, 1H), 7.38-7.31(m, 2H), 7.29 (d, 1H), 7.12-7.01 (m, 2H), 6.90 (d, 1H), 6.61 (dd, 1H),6.31 (dd, 1H), 6.25 (d, 1H), 5.85 (d, 1H), 4.40 (s, 1H), 3.92 (s, 4H),3.17-2.89 (m, 8H), 2.73 (s, 4H), 2.38 (s, 3H), 2.18 (m, 6H), 1.96 (s,2H), 1.80 (m, 2H), 1.57 (s, 2H), 1.39 (s, 2H), 1.22 (m, 2H), 0.96 (m,6H).

Example 3134-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,4-difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 313A3,4-difluoro-5-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

The title compound was obtained as a side product in EXAMPLE 310A.

Example 313B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3,4-difluoro-5-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 313A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (400 MHz,pyridine-d₅) δ 13.05 (s, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.98 (m, 2H),7.66 (m, 1H), 7.63 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.77 (dd, 1H),6.54 (d, 1H), 6.48 (dd, 1H), 4.12 (d, 2H), 3.83 (m, 2H), 3.75 (m, 2H),3.08 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.15 (m, 4H), 1.97 (s, 2H),1.82 (m, 4H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 314N-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 314A(S)-5-chloro-6-((4-cyclopropylmorpholin-2-yl)methoxy)pyridine-3-sulfonamide

A solution of EXAMPLE 244B (250 mg), anhydrous methanol (6 mL),(1-ethoxycyclopropoxy)trimethylsilane (0.474 mL), and acetic acid (0.509mL) was heated at 70° C. for 30 minutes. After cooling to ambienttemperature, sodium cyanoborohydride (112 mg) was added and the mixturewas stirred for 18 hours. Additional sodium cyanoborohydride (75 mg) wasadded and stirring was continued 18 hours. The reaction was concentratedand the residue was partitioned between methylene chloride and saturatedsodium bicarbonate solution. The crude product was isolated from thedried methylene chloride layer and was purified on silica gel and waseluted with a 1, 2.5, 5, 10% methanol in methylene chloride stepgradient to provide the title compound.

Example 314BN-[(5-chloro-6-{[(2S)-4-cyclopropylmorpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 314A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (400 MHz, pyridine-d₅) δ 12.98 (s, 1H),9.09 (d, 1H), 8.69 (d, 1H), 8.41 (d, 1H), 8.11 (d, 1H), 7.66-7.64 (m,2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.75 (dd, 1H), 6.53 (m, 1H), 6.48 (m,1H), 5.72 (br s, 1H), 4.62-4.57 (m, 1H), 4.51-4.47 (m, 1H), 3.99 (m,1H), 3.85 (m, 1H), 3.57 (m, 1H), 3.08-3.01 (m, 5H), 2.77 (s, 2H), 2.69(m, 1H), 2.39-2.24 (m, 4H), 2.14 (m, 4H), 1.97 (s, 2H), 1.57 (m, 1H),1.39 (t, 2H), 0.94 (m, 6H), 0.48-0.3 (m, 4H).

Example 3154-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 302C for EXAMPLE1E and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.70 (s, 1H), 11.35 (br s, 1H), 8.61 (m, 1H),8.57 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.45-7.57 (m, 3H), 7.33 (d,2H), 7.15 (d, 1H), 7.01 (d, 2H), 6.65 (dd, 1H), 6.40 (dd, 1H), 6.11 (d,1H), 3.85 (dd, 2H), 3.53 (m, 2H), 3.27 (m, 4H), 2.63 (m, 2H), 2.04 (m,2H), 1.91 (s, 2H), 1.77 (m, 2H), 1.62 (m, 4H), 1.45 (m, 2H), 1.38 (m,2H), 1.27 (m, 1H), 1.23 (m, 4H), 0.92 (s, 6H).

Example 3164-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-{[3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 316A3-chloro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

The title compound was prepared by substituting(tetrahydro-2H-pyran-4-yl)methanol for(4-fluoro-1-methylpiperidin-4-yl)methanol in EXAMPLE 283A.

Example 316B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperidin-1-yl)-N-{[3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 302C for EXAMPLE1E and EXAMPLE 316A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.77 (s, 1H), 11.35 (br s, 1H), 8.06 (m, 1H),7.88 (d, 1H), 7.79 (dd, 1H), 7.58 (s, 1H), 7.53 (t, 1H), 7.46 (d, 1H),7.34 (d, 2H), 7.22 (d, 1H), 7.01 (d, 2H), 6.66 (dd, 1H), 6.42 (dd, 1H),6.11 (d, 1H), 3.99 (d, 2H), 3.88 (dd, 2H), 3.52 (m, 2H), 3.34 (m, 4H),2.62 (m, 2H), 2.04 (m, 4H), 1.76 (m, 2H), 1.68 (m, 2H), 1.46 (m, 2H),1.38 (m, 4H), 0.92 (s, 6H), 0.75 (m, 2H).

Example 317 methyl2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholine-4-carboxylateExample 317A methyl2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting methyl chloroformate formethyl iodide in EXAMPLE 134B.

Example 317B methyl2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 317A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (d, 1H), 8.84 (t, 1H), 8.43 (d, 1H), 8.35 (d, 1H), 8.12 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (bs, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 4.29-4.03 (m, 1H), 3.89-3.70 (m, 3H), 3.71(s, 3H), 3.55-3.38 (m, 3H), 3.07 (m, 4H), 2.96 (dt, 1H), 2.86 (dd, 1H),2.77 (s, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H),0.94 (s, 6H).

Example 3182-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamideExample 318AN-ethyl-N-methyl-2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxamide

The title compound was prepared by substituting N-methyl-N-ethylcarbamyl chloride for methyl iodide in EXAMPLE 134B.

Example 318B2-{[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide

The title compound was prepared by substituting EXAMPLE 318A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (d, 1H), 8.86 (t, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.12 (d, 1H),7.67 (t, 1H), 7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.91 (d, 1H),6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.92-3.85 (m, 2H), 3.75 (d,1H), 3.62 (dt, 1H), 3.55-3.48 (m, 1H), 3.45-3.39 (m, 2H), 3.21 (q, 2H),3.07 (m, 4H), 2.99 (dt, 1H), 2.90 (dd, 1H), 2.77 (s, 2H), 2.76 (s, 3H),2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 1.06 (t, 3H),0.93 (s, 6H).

Example 3194-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 319A4-((4-(methylsulfonyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting methanesulfonyl chloridefor methyl iodide in EXAMPLE 134B.

Example 319B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 319A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.25 (d, 1H), 8.84 (t, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.13 (d, 1H),7.67 (t, 1H), 7.65 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.92 (d, 1H),6.75 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 3.99 (m, 1H), 3.92-3.88 (m,2H), 3.64 (m, 2H), 3.56 (m, 1H), 3.50 (m, 1H), 3.07 (m, 4H), 3.04 (s,3H), 2.95-2.88 (m, 2H), 2.77 (s, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97(s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 3204-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 320A4-(3-(cyclobutyl(cyclopropyl)amino)propylamino)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 308A (314 mg) in dichloromethane (5 mL) wasadded cyclobutanone (70 mg) followed by sodium triacetoxyborohydride(318 mg). The mixture was stirred overnight. The mixture was dilutedwith dichloromethane (300 mL) and washed with aqueous NaHCO₃, water andbrine and dried over Na₂SO₄. After filtration, evaporation of solventgave the title compound.

Example 320B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({3-[cyclobutyl(cyclopropyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 320A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 8.70 (m, 1H), 8.54 (d, 1H), 8.02(d, 1H), 7.79 (dd, 1H), 7.49 (m, 3H), 7.34 (d, 2H), 7.03 (m, 3H), 6.66(dd, 1H), 6.38 (dd, 1H), 6.19 (d, 1H), 3.37 (q, 2H), 3.06 (m, 4H), 2.73(s, 2H), 2.63 (m, 2H), 2.21 (m, 8H), 1.82 (m, 3H), 1.53 (m, 2H), 1.38(t, 2H), 0.94 (m, 6H), 0.41 (m, 4H).

Example 3214-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 321A ethyl 5,5-difluoro-2-oxocyclohexanecarboxylate

To a solution of diethyl 4,4-difluoroheptanedioate (4.3 g) in toluene(50 mL) was added potassium 2-methylpropan-2-olate (2.87 g) and thereaction stirred overnight at room temperature. The reaction wasquenched with 1N aqueous HCl (100 mL) and extracted with diethyl ether(150 mL). The ether layer was washed with brine (50 mL), dried overmagnesium sulfate, filtered, and concentrated. Silica gel chromatography(Reveleris 40 g) eluting with a gradient of 1% to 5% ethylacetate/hexanes gave the title compound.

Example 321B ethyl5,5-difluoro-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a solution of EXAMPLE 321A (2.37 g) in dichloromethane (40 mL) at 0°C. was added N,N-diisopropylethylamine (5.02 mL) followed bytrifluoromethanesulfonic anhydride (2.33 mL) and the reaction wasallowed to slowly warm to room temperature. After stirring overnight thereaction was quenched with 10 ml of water then 1N aqueous HCl (100 mL).The reaction was extracted with dichloromethane (3×75 mL), and thecombined organics were washed with brine (50 mL) and concentrated.Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 1%to 25% ethyl acetate/hexanes gave the title compound.

Example 321C ethyl2-(4-chlorophenyl)-5,5-difluorocyclohex-1-enecarboxylate

A solution of EXAMPLE 321B (3.47 g), 4-chlorophenylboronic acid (1.925g) and cesium fluoride (3.43 g) in 30 ml of 1,2-dimethoxyethane and 15ml of ethanol was degassed with nitrogen for 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.237 g) was added and thereaction was heated to 70° C. The reaction was diluted with ether (200mL) and washed with 1N aqueous HCl (100 mL) and brine (100 mL), driedover magnesium sulfate, filtered, and concentrated. Silica gelchromatography (Reveleris 40 g) eluting with a gradient of 1% to 8%ethyl acetate/hexanes over 40 minutes gave the title compound.

Example 321D (2-(4-chlorophenyl)-5,5-difluorocyclohex-1-enyl)methanol

To a solution of EXAMPLE 321C (1.84 g) in diethyl ether (25 mL) at 0° C.was added lithium aluminum hydride (1.0M, 4.28 mL). The reaction wasquenched with the dropwise addition of water, then 1N aqueous HCl (50mL) was added and the reaction diluted with diethyl ether (100 mL). Theorganic layer was separated, washed with brine (50 mL) dried overmagnesium sulfate, filtered and concentrated to provide the titlecompound.

Example 321E 2-(4-chlorophenyl)-5,5-difluorocyclohex-1-enecarbaldehyde

To a solution of EXAMPLE 321D (1.38 g) in dichloromethane (25 mL) wasadded Dess-Martin periodinane (2.489 g) and the reaction stirred for 1hour at room temperature. The reaction was quenched with 1N aqueous NaOHsolution (75 mL) and the product was extracted into dichloromethane(2×100 mL). The combined organics were washed with brine (75 mL), driedover magnesium sulfate, filtered, and concentrated. Silica gelchromatography (REVELERIS 80 g) eluting with a gradient of 1% to 10%ethyl acetate/hexanes over 40 minutes gave the title compound.

Example 321F methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-difluorocyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 321E for EXAMPLE15E in EXAMPLE 15G.

Example 321G2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-difluorocyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 321F for EXAMPLE15G in EXAMPLE 15H.

Example 321H4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 321G for EXAMPLE1E and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.74-11.63 (m, 1H), 11.53-11.29 (m, 1H), 8.57(d, 2H), 8.05 (d, 1H), 7.85-7.77 (m, 1H), 7.49 (d, 3H), 7.38 (d, 2H),7.16-7.06 (m, 3H), 6.73-6.64 (m, 1H), 6.43-6.36 (m, 1H), 6.21-6.14 (m,1H), 3.93-3.77 (m, 2H), 3.29 (d, 4H), 3.07 (s, 4H), 2.79-2.57 (m, 4H),2.45 (dd, 2H), 2.19 (s, 6H), 1.99-1.80 (m, 1H), 1.70-1.54 (m, 2H),1.38-1.13 (m, 2H).

Example 322N-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 322A tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (2 g) wastaken up in tetrahydrofuran (20 ml) and cooled in an ice bath. Lithiumaluminum hydride (1.0M in dioxane, 5.09 mL) was added dropwise. Thereaction was stirred at room temperature for 2 hours. The reaction wasquenched with water and with 1M aqueous NaOH solution and then stirredanother 1 hour at room temperature. The mixture was extracted with ethylacetate, and the extracts were combined and washed with water and withbrine, dried over MgSO₄, filtered and concentrated under vacuum. Thecrude product was used without further purification.

Example 322B tert-butyl4-((2-chloro-4-sulfamoylphenoxy)methyl)-4-fluoropiperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 322A for(tetrahydro-2H-pyran-4-yl)methanol and3-chloro-4-fluorobenzenesulfonamide for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 322C3-chloro-4-((4-fluoropiperidin-4-yl)methoxy)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 322B for EXAMPLE1A in EXAMPLE 1B.

Example 322D3-chloro-4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)benzenesulfonamide

To a solution of EXAMPLE 322C (830 mg) in tetrahydrofuran (15 mL) andacetic acid (5 mL) was added oxetan-3-one (163 mg) andMP-cyanoborohydride (2.38 mmol/g, 1.9 g). The mixture was stirred atroom temperature overnight. The reaction was then filtered and thefiltrate was concentrated under vacuum. The residue was slurried inether and the solid product was collected by filtration.

Example 322EN-[(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 322D for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.71 (s, 1H), 8.06 (d, 1H), 7.89 (d, 1H), 7.79(m, 1H), 7.58 (d, 1H), 7.52 (t, 1H), 7.49 (d, 1H), 7.34 (d, 2H), 7.25(d, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.42 (m, 1H), 6.18 (d, 1H), 4.55(t, 2H), 4.44 (t, 2H), 4.24 (d, 2H), 3.44 (m, 2H), 3.07 (br s, 4H), 2.74(m, 2H), 2.59 (m, 2H), 2.14 (m, 7H), 1.95 (m, 4H), 1.78 (m, 2H), 1.38(t, 2H), 0.92 (s, 6H).

Example 3234-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 323A3-chloro-4-((tetrahydrofuran-3-yl)methoxy)benzenesulfonamide

The title compound was prepared by substituting4-fluoro-3-chlorobenzenesulfonamide for4-fluoro-3-nitrobenzenesulfonamide and (tetrahydrofuran-3-yl)methanolfor (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A, except here,dimethylformamide was used in place of tetrahydrofuran and the reactionwas heated at 70° C. for two days.

Example 323B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-chloro-4-(tetrahydrofuran-3-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 323A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.73 (s,1H), 8.07 (d, 1H), 7.89 (d, 1H), 7.80 (dd, 1H), 7.59 (d, 1H), 7.51 (dd,1H), 7.49 (d, 1H), 7.34 (d, 2H), 7.23 (d, 1H), 7.03 (d, 2H), 6.66 (dd,1H), 6.42 (m, 1H), 6.19 (d, 1H), 4.07 (m, 2H), 3.80 (m, 2H), 3.68 (m,1H) 3.56 (m, 1H), 3.10 (br m, 4H), 2.85 (br s, 2H), 2.69 (m, 1H), 2.32(br m, 4H), 2.17 (br m, 2H), 2.02 (m, 1H), 1.96 (s, 2H), 1.69 (m, 1H),1.40 (t, 2H), 0.92 (s, 6H).

Example 3244-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 324A4-((trans-4-hydroxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 120A for EXAMPLE39B in EXAMPLE 39C.

Example 324B4-(4-{[2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 321G for EXAMPLE1E and EXAMPLE 324A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.41 (s, 1H), 8.65-8.50 (m, 2H),8.05 (d, 1H), 7.80 (dd, 1H), 7.60-7.44 (m, 3H), 7.41-7.34 (m, 2H),7.14-7.02 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.17 (d, 1H), 4.50 (d,1H), 3.23 (t, 2H), 3.06 (s, 4H), 2.70 (d4H), 2.44 (s, 2H), 2.33-1.94 (m,6H), 1.78 (dd, 4H), 1.51 (d, 2H), 1.23 (s, 2H), 1.16-0.92 (m, 2H).

Example 325N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 325A methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting oxetan-3-one for1,3-difluoropropan-2-one in EXAMPLE 265G.

Example 325B2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 325A for EXAMPLE15G in EXAMPLE 15H.

Example 325CN-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 325B for EXAMPLE1E and EXAMPLE 286A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.13 (s, 1H), 8.05 (d, 1H), 7.87(d, 1H), 7.80-7.70 (m, 1H), 7.59-7.46 (m, 3H), 7.34 (d, 2H), 7.21 (d,1H), 7.11-7.03 (m, 2H), 6.66 (d, 1H), 6.41 (dd, 1H), 6.18 (d, 1H), 4.50(dd, 4H), 4.26 (d, 2H), 3.85-3.69 (m, 2H), 3.61 (d, 3H), 3.05 (s, 4H),2.69 (s, 2H), 2.37 (s, 4H), 2.17 (s, 6H), 2.04 (s, 2H), 1.87 (d, 4H),1.49 (d, 6H).

Example 3264-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 326A(R)-4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 258E for EXAMPLE173A in EXAMPLE 173B.

Example 326B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 326A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (d, 1H), 8.88 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 3.88 (d, 1H), 3.84-3.81 (m, 1H), 3.59 (dt,1H), 3.50-3.40 (m, 2H), 3.07 (m, 4H), 2.93 (d, 1H), 2.77 (s, 2H), 2.69(d, 1H), 2.34 (dt, 1H), 2.26 (m, 2H), 2.21 (t, 1H), 2.14 (m, 4H), 1.97(s, 2H), 1.58 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H), 0.45-0.39 (m, 4H).

Example 3274-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 327A(S)-4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 259E for EXAMPLE173A in EXAMPLE 173B.

Example 327B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-cyclopropylmorpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 327A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (d, 1H), 8.88 (t, 1H), 8.44 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.94 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 3.88 (d, 1H), 3.84-3.81 (m, 1H), 3.59 (dt,1H), 3.50-3.40 (m, 2H), 3.07 (m, 4H), 2.93 (d, 1H), 2.77 (s, 2H), 2.69(d, 1H), 2.34 (dt, 1H), 2.26 (m, 2H), 2.21 (t, 1H), 2.14 (m, 4H), 1.97(s, 2H), 1.58 (m, 1H), 1.39 (t, 2H), 0.94 (s, 6H), 0.45-0.39 (m, 4H).

Example 3284-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 328A spiro[2.5]octan-5-one

To a solution of 3-ethoxycyclohex-2-enone (48.1 mL) in ether (1000 mL)was added titanium(IV) isopropoxide (110 mL) followed by addition ofethylmagnesium bromide (357 mL) at ambient temperature. The reactionmixture was stirred for 2 hours at ambient temperature and was thenquenched with water (500 mL). The organic layer was separated (decanted)and the water layer was extracted with ether (3×300 mL). The combinedextracts were partially concentrated to approximately 300 mL.p-Toluenesulfonic acid monohydrate (3.0 g) was added and the reactionmixture was stirred overnight at ambient temperature. The reactionmixture was then washed with saturated aqueous NaHCO₃ solution, dried(MgSO₄), filtered and concentrated. The concentrate was purified byfractional distillation (1st fraction b.p. 27° C. at 23 torr (notproduct), 2nd fraction (product) b.p. 75° C. at 8 torr).

Example 328B 5-chlorospiro[2.5]oct-5-ene-6-carbaldehyde

N,N-dimethylformamide (2.1 mL) in dichloromethane (3.2 ml) at −5° C. wastreated slowly with POCl₃ (2.33 ml) keeping the bath temperature lessthan 0° C. The cooling bath was removed and the mixture was stirred atambient temperature for 30 minutes. The reaction mixture was returned tothe cooling bath and EXAMPLE 328A (2.484 g) in dichloromethane (4 mL)was added slowly to the reaction mixture. The reaction mixture washeated at 45° C. for 15 hours, cooled to room temperature and thenpoured into a mixture of ice and saturated aqueous sodium acetatesolution. After the ice melted, the mixture was extracted with diethylether. The combined extracts were washed with saturated aqueous NaHCO₃solution and brine, dried (MgSO₄), filtered and concentrated. Theconcentrate was chromatographed with 0 to 10% CH₂Cl₂ in hexanes, then25% CH₂Cl₂ in hexanes and then 100% CH₂Cl₂ as the eluents.

Example 328C 5-(4-chlorophenyl)spiro[2.5]oct-5-ene-6-carbaldehyde

EXAMPLE 328B (2.9 g), 4-chlorophenylboronic acid (2.87 g), palladium(II)acetate (0.103 g), K₂CO₃ (5.28 g) and tetrabutylammonium bromide (4.93g) were combined in a 100-mL round bottomed flask with water (17.0 mL).The flask was flushed with nitrogen and stirred at 45° C. for 14 hours.The reaction mixture was partitioned between brine and diethyl ether.The organic layer was washed with brine, dried (MgSO₄), filtered througha plug of celite, concentrated and chromatographed on silica gel with 0to 2% ethyl acetate in hexanes as the eluent.

Example 328D methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 15F fortert-butyl piperazine carboxylate and EXAMPLE 328C for4-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 328E2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl)methyl)piperazin-1-yl)benzoicacid hydrochloride

EXAMPLE 328D (0.85 g) in a mixture of tetrahydrofuran (4.8 mL), methanol(2.4 mL) and water (2.4 mL) was treated with LiOH.H₂O (0.184 g) andheated overnight at 50° C. The reaction mixture was cooled to roomtemperature, concentrated to remove tetrahydrofuran and methanol andacidified with 1 N aqueous HCl causing precipitation of the product. Thesolid was collected by filtration, rinsed with water and dried overnightin a vacuum oven at 80° C. to provide the title compound.

Example 328F4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 328E for EXAMPLE1E in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-d₅) δ 13.07 (s, 1H), 9.32(d, 1H), 8.68 (t, 1H), 8.44 (d, 1H), 8.38 (dd, 1H), 8.10 (d, 1H), 7.68(m, 1H), 7.66 (d, 1H), 7.43 (m, 2H), 7.10 (m, 2H), 6.91 (d, 1H), 6.75(dd, 1H), 6.51 (m, 2H), 3.97 (dd, 2H), 3.30 (td, 2H), 3.16 (t, 2H), 3.06(m, 4H), 2.81 (s, 2H), 2.37 (t, 2H), 2.16 (m, 4H), 2.11 (s, 2H), 1.81(m, 1H), 1.58 (dd, 2H), 1.45 (t, 2H), 1.32 (qd, 2H), 0.38 (s, 4H).

Example 329N-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 329A ethyl 4-(cyclopropylamino)cyclohexanecarboxylate

To a solution of ethyl 4-oxocyclohexanecarboxylate (3.4 g) indichloromethane (30 mL) was added cyclopropanamine (1.14 g) followed bysodium triacetoxyborohydride (4.24 g). The mixture was stirredovernight. The mixture was diluted with dichloromethane (300 mL) andwashed with 2N NaOH, water, brine and dried over Na₂SO₄. Filtration andevaporation of the solvent gave the title compound.

Example 329B ethyl4-(cyclopropyl(oxetan-3-yl)amino)cyclohexanecarboxylate

To a solution of EXAMPLE 329A (1.05 g) in dichloromethane (10 mL) wasadded oxetan-3-one (0.358 g) followed by sodium triacetoxyborohydride(1.05 g). The mixture was stirred overnight. The mixture was dilutedwith dichloromethane (300 mL) and washed with 2N aqueous NaOH, water,brine and dried over Na₂SO₄. Filtration and evaporation of the solventgave the title compound.

Example 329C (4-(cyclopropyl(oxetan-3-yl)amino)cyclohexyl)methanol

To a solution of EXAMPLE 329B (1.2 g) in tetrahydrofuran (20 mL) wasadded lithium aluminum hydride (0.681 g). The mixture was stirredovernight. 2N aqueous NaOH solution was added dropwise to the reactionmixture. The mixture was then diluted with ethyl acetate (300 mL) andwashed with water, brine and dried over Na₂SO₄. Filtration andevaporation of the solvent gave the title compound.

Example 329D5-chloro-6-((4-(cyclopropyl(oxetan-3-yl)amino)cyclohexyl)methoxy)pyridine-3-sulfonamide

To a solution of EXAMPLE 329C (706 mg) in N,N-dimethylformamide (6 mL)was added NaH (60% in mineral oil, 300 mg). The mixture was stirred for30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (706 mg) wasadded. The mixture was stirred overnight. The mixture was poured overaqueous NH₄Cl and extracted with ethyl acetate (3×200 mL). The combinedorganic layers were washed with water, brine and dried over Na₂SO₄.After filtration and evaporation of the solvent the residue was loadedon a silica gel cartridge and eluted with 5 to 10% 7N NH₃ in methanol indichloromethane to provide the title compound.

Example 329EN-{[5-chloro-6-({4-[cyclopropyl(oxetan-3-yl)amino]cyclohexyl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 329D for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.64 (s, 1H), 8.50 (m, 1H), 8.16 (s, 1H), 8.02(d, 1H), 7.51 (m, 3H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38(m, 1H), 6.21 (s, 1H), 4.70 (m, 2H), 4.43 (t, 3H), 4.19 (m, 2H), 3.12(m, 4H), 2.84 (m, 2H), 2.19 (m, 6H), 1.96 (s, 3H), 1.77 (m, 3H), 1.38(m, 7H), 0.93 (s, 6H), 0.44 (m, 4H).

Example 3304-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 328E for EXAMPLE3J and EXAMPLE 218A for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (400 MHz,pyridine-d₅) δ 13.01 (s, 1H), 9.26 (d, 1H), 8.88 (t, 1H), 8.43 (d, 1H),8.34 (dd, 1H), 8.11 (d, 1H), 7.66 (m, 2H), 7.42 (m, 2H), 7.09 (m, 2H),6.95 (d, 1H), 6.75 (dd, 1H), 6.53 (d, 1H), 6.49 (dd, 1H), 3.84 (m, 2H),3.58 (td, 1H), 3.45 (m, 2H), 3.06 (m, 4H), 2.93 (d, 1H), 2.81 (s, 2H),2.69 (d, 1H), 2.35 (m, 3H), 2.19 (m, 5H), 2.11 (s, 2H), 1.58 (m, 1H),1.45 (t, 2H), 0.42 (m, 8H).

Example 331N-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 331A tert-butyl2-((2-chloro-4-sulfamoylphenoxy)methyl)morpholine-4-carboxylate

To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate(0.478 g) in anhydrous N,N-dimethylformamide (5 mL) was added sodiumhydride (0.280 g). The mixture was stirred at room temperature for 30minutes, followed by addition of 3-chloro-4-fluorobenzenesulfonamide(0.419 g). The mixture was stirred at 40° C. overnight. The reaction wasquenched with water (10 mL), and the mixture was adjusted to ˜pH 7 andextracted with ethyl acetate. The crude product was purified on a silicagel column eluting with 60% ethyl acetate in hexane to provide the titlecompound.

Example 331B 3-chloro-4-(morpholin-2-ylmethoxy)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 331A for EXAMPLE113A in EXAMPLE 134A.

Example 331C3-chloro-4-((4-cyclopropylmorpholin-2-yl)methoxy)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 331B for EXAMPLE173A in EXAMPLE 173B.

Example 331DN-({3-chloro-4-[(4-cyclopropylmorpholin-2-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 331C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.04 (s, 1H),8.54 (d, 1H), 8.43 (d, 1H), 8.27 (dd, 1H), 8.09 (d, 1H), 7.66 (m, 2H),7.44 (d, 2H), 7.07 (d, 2H), 7.05 (d, 1H), 6.75 (dd, 1H), 6.52 (d, 1H),6.50 (m, 1H), 4.20 (dd, 1H), 4.10 (dd, 1H), 3.94 (m, 1H), 3.86 (d, 1H),3.58 (dt, 1H), 3.06 (m, 5H), 2.77 (s, 2H), 2.69 (d, 1H), 2.40-2.20 (m,4H), 2.14 (m, 4H), 1.97 (s, 2H), 1.60 (m, 1H), 1.39 (t, 2H), 0.94 (s,6H), 0.41 (m, 4H).

Example 332N-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 332A tert-butyl2-((2-chloro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

A solution of 3-chloro-4-fluorobenzenesulfonamide (1.0 g), tert-butyl2-(aminomethyl)morpholine-4-carboxylate (1.135 g) andN-ethyl-N-isopropylpropan-2-amine (1.246 mL) in dimethylsulfoxide (15mL) was stirred at 115° C. for 72 hours. The mixture was concentrated,and the residue was purified on a silica gel column eluting with 60%ethyl acetate to provide the title compound.

Example 332B 3-chloro-4-(morpholin-2-ylmethylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 332A for EXAMPLE113A in EXAMPLE 134A.

Example 332C

The title compound was prepared by substituting EXAMPLE 332B for EXAMPLE173A in EXAMPLE 173B.

Example 332DN-[(3-chloro-4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 332C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.05 (s, 1H),8.45 (m, 2H), 8.21 (dd, 1H), 8.12 (d, 1H), 7.69 (d, 1H), 7.67 (t, 1H),7.44 (d, 2H), 7.07 (d, 2H), 6.78 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H),6.50 (m, 1H), 6.37 (m, 1H), 3.84 (d, 1H), 3.77 (m, 1H), 3.54 (dt, 1H),3.35 (m, 2H), 3.05 (m, 4H), 2.94 (d, 1H), 2.77 (s, 2H), 2.68 (d, 1H),2.32 (dt, 1H), 2.26 (m, 2H), 2.18-2.12 (m, 5H), 1.97 (s, 2H), 1.55 (m,1H), 1.39 (t, 2H), 0.94 (s, 6H), 0.41 (m, 4H).

Example 3332-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}phenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamideExample 333A2-((2-chloro-4-sulfamoylphenylamino)methyl)-N-ethyl-N-methylmorpholine-4-carboxamide

The title compound was prepared by substituting EXAMPLE 332B for EXAMPLE134A and N-methyl-N-ethyl carbamyl chloride for methyl iodide in EXAMPLE134B.

Example 333B2-{[(2-chloro-4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}phenyl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide

The title compound was prepared by substituting EXAMPLE 333A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.05 (s, 1H),8.46 (s, 1H), 8.45 (s, 1H), 8.20 (dd, 1H), 8.10 (d, 1H), 7.69 (d, 1H),7.67 (t, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.79 (d, 1H), 6.73 (dd, 1H),6.52 (dd, 1H), 6.49 (d, 1H), 6.43 (m, 1H), 3.83 (d, 2H), 3.73 (d, 1H),3.59 (dt, 1H), 3.41-3.35 (m, 3H), 3.20 (q, 2H), 3.05 (m, 4H), 2.95 (t,1H), 2.84 (dd, 1H), 2.76 (s, 2H), 2.73 (s, 3H), 2.25 (m, 2H), 2.14 (m,4H), 1.97 (s, 2H), 1.39 (t, 2H), 1.04 (t, 3H), 0.94 (s, 6H).

Example 334(2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-carboxamideExample 334A(S)-2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-N-ethyl-N-methylmorpholine-4-carboxamide

The title compound was prepared by substituting EXAMPLE 244B for EXAMPLE134A and N-methyl-N-ethyl carbamyl chloride for methyl iodide in EXAMPLE134B.

Example 334B(2S)-2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)oxy]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide

The title compound was prepared by substituting EXAMPLE 334A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 12.98 (s, 1H),9.08 (d, 1H), 8.70 (d, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.67 (t, 1H),7.64 (d, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.75 (dd, 1H), 6.53 (d, 1H),6.48 (m, 1H), 4.58 (dd, 1H), 4.47 (dd, 1H), 4.03 (m, 1H), 3.84 (m, 2H),3.63 (dt, 1H), 3.45 (d, 1H), 3.22 (q, 2H), 3.07 (m, 4H), 3.05-2.95 (m,2H), 2.78 (s, 3H), 2.77 (s, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s,2H), 1.39 (t, 2H), 1.07 (t, 3H), 0.94 (s, 6H).

Example 335N-[(5-chloro-6-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 335A tert-butyl2-((3-chloro-5-sulfamoylpyridin-2-ylamino)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide and tert-butyl2-(aminomethyl)morpholine-4-carboxylate for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 335B5-chloro-6-(morpholin-2-ylmethylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 335A for EXAMPLE113A in EXAMPLE 134A.

Example 335C5-chloro-6-((4-cyclopropylmorpholin-2-yl)methylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 335B for EXAMPLE173A in EXAMPLE 173B.

Example 335DN-[(5-chloro-6-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 335C for EXAMPLE130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine-d₅) δ 13.02 (s, 1H),9.15 (d, 1H), 8.49 (d, 1H), 8.43 (d, 1H), 8.11 (d, 1H), 7.80 (t, 1H),7.69 (d, 1H), 7.65 (t, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.73 (dd, 1H),6.52 (m, 1H), 6.49 (d, 1H), 3.92 (m, 1H), 3.84 (m, 2H), 3.70 (m, 1H),3.54 (dt, 1H), 3.05 (m, 4H), 2.99 (d, 1H), 2.76 (s, 2H), 2.68 (d, 1H),2.32 (dt, 1H), 2.25 (m, 2H), 2.12 (m, 5H), 1.97 (s, 2H), 1.53 (m, 1H),1.39 (t, 2H), 0.93 (s, 6H), 0.40 (m, 4H).

Example 3362-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamideExample 336A2-((3-chloro-5-sulfamoylpyridin-2-ylamino)methyl)-N-ethyl-N-methylmorpholine-4-carboxamide

The title compound was prepared by substituting EXAMPLE 335B for EXAMPLE134A and N-methyl-N-ethyl carbamyl chloride for methyl iodide in EXAMPLE134B.

Example 336B2-{[(3-chloro-5-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}pyridin-2-yl)amino]methyl}-N-ethyl-N-methylmorpholine-4-carboxamide

The title compound was prepared by substituting EXAMPLE 336A for EXAMPLE130C in EXAMPLE 130D. 1H NMR (500 MHz, pyridine-d₅) δ 13.03 (s, 1H),9.14 (d, 1H), 8.51 (d, 1H), 8.43 (d, 1H), 8.11 (d, 1H), 7.89 (m, 1H),7.69 (d, 1H), 7.66 (t, 1H), 7.44 (d, 2H), 7.07 (d, 2H), 6.74 (dd, 1H),6.51 (m, 1H), 6.48 (d, 1H), 3.96 (m, 1H), 3.90-3.70 (m, 4H), 3.59 (dt,1H), 3.43 (d, 1H), 3.17 (q, 2H), 3.05 (m, 4H), 2.95 (dt, 1H), 2.81 (dd,1H), 2.76 (s, 2H), 2.72 (s, 3H), 2.25 (m, 2H), 2.13 (m, 4H), 1.97 (s,2H), 1.39 (t, 2H), 1.03 (t, 3H), 0.93 (s, 6H).

Example 3374-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 337A methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoromethanesulfonic anhydride (40 mL) was added. Thereaction mixture was warmed to room temperature and stirred for 24hours. The organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated to give the product.

Example 337B methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 337A (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether (4×200 mL) was added and the mixturewas filtered. The combined ether solution was concentrated to give theproduct.

Example 337C (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 337B (53.8 g) and ether (400 mL),was added methanol (25 mL) slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted withether (3×100 mL). The extracts were dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with0-30% ethyl acetate/hexanes.

Example 337D tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 337C (29.3 g)and triethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C., and the mixturewas stirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was addedand the mixture was stirred at room temperature for 24 hours. Thesuspension was washed with brine, dried, (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with10-20% ethyl acetate/hexanes.

Example 337E1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

EXAMPLE 337D (1 g) was stirred in dichloromethane (10 mL),trifluoroacetic acid (10 mL), and triethylsilane (1 mL) for 1 hour. Themixture was concentrated, taken up in a mixture of dichloromethane (100mL) and saturated aqueous Na₂CO₃ solution (20 mL) and stirred for 10minutes. The layers were separated, and the organic layer was dried overNa₂SO₄, and concentrated to give the product.

Example 337F 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) intetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide intetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl(triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirredat room temperature for 24 hours. The reaction was diluted with ether,and the resulting solution was washed twice with water. The extractswere dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 10% ethyl acetate/hexanes.

Example 337G 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

To a mixture of EXAMPLE 337F (24.3 g) in tetrahydrofuran (500 mL) at−78° C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate(11.5 mL) was added, and the mixture was allowed to warm to roomtemperature over 1 hour. The reaction was poured into water, extractedthree times with ethyl acetate, and the combined extracts were washedwith brine and concentrated. The crude product was taken up intetrahydrofuran (200 mL) at 0° C., and 1M aqueous NaOH (69 mL) wasadded, followed by 30% aqueous H₂O₂ (8.43 mL), and the solution wasstirred for 1 hour. Na₂S₂O₃ (10 g) was added, and the pH was adjusted to4-5 with concentrated HCl and solid NaH₂PO₄. The solution was extractedtwice with ethyl acetate, and the combined extracts were washed withbrine, dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 5-25% ethyl acetate/hexanes.

Example 337H methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate

A mixture of EXAMPLE 337G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The crude product waschromatographed on silica gel with 2-50% ethyl acetate/hexanes.

Example 337I methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of EXAMPLE 337H (1.55 g), EXAMPLE 337E (2.42 g), and HK₂PO₄(1.42 g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24hours. The reaction was cooled, diluted with ether (400 mL), and washedthree times with 1M aqueous NaOH, and brine, and concentrated. The crudeproduct was chromatographed on silica gel with 10-50% ethylacetate/hexanes.

Example 337J2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 337I (200 mg) in dioxane (10 mL) and 1M aqueous NaOH (6 mL) at50° C. was stirred for 24 hours. The reaction was cooled, added toNaH₂PO₄ solution, and extracted three times with ethyl acetate. Thecombined extracts were washed with brine, and concentrated to give thepure product.

Example 337K tert-butyl (4-hydroxy-4-methylcyclohexyl)methylcarbamate

To a vigorous stirring solution of tert-butyl(4-oxocyclohexyl)methylcarbamate (1.7 g) in tetrahydrofuran (40 mL) at−78° C. was dropwise added 1.6 M methyllithium (14.02 mL) in ether.After completion of the addition, the mixture was stirred at −78° C. for1.2 hours and poured into a cold NH₄Cl aqueous solution. The resultingmixture was extracted with dichloromethane (100 ml, three times) and theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was dissolved in dichloromethane and loaded onto an Analogixpurification system, and it was eluted with 0-50% ethyl acetate indichloromethane to provide the title compound.

Example 337L 4-(aminomethyl)-1-methylcyclohexanol

EXAMPLE 337K (1.3 g) in dichloromethane (5 mL) at 0° C. was treated withtrifluoroacetic acid (2.1 mL) and a few drops of water for 1 hour. Thereaction mixture was concentrated and the residue was directly used fornext step.

Example 337M4-((trans-4-hydroxy-4-methylcyclohexyl)methylamino)-3-nitrobenzenesulfonamide

EXAMPLE 337L (732 mg) and 4-fluoro-3-nitrobenzenesulfonamide (1.1 g) intetrahydrofuran (15 mL) was treated with triethylamine overnight. Thereaction mixture, was concentrated and the residue was purified by areverse phase chromatography, eluting with 30%-50% acetonitrile in 0.1%trifluoroacetic acid water solution to isolate the title compound.

Example 337N4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A mixture of EXAMPLE 337J (3.0 g), EXAMPLE 337M (1.98 g), N,N-dimethylpyridin-4-amine (1.93 g) andN¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (1.31 g) in dichloromethane (50 ml) was stirred overnightand concentrated. The residue was purified by reverse chromatography,eluted with 40%-70% acetonitrile in 0.1% TFA water. The desiredfractions were concentrated to remove acetonitrile, neutralized withNaHCO₃ and extracted with dichloromethane. The organic layer was driedover Na₂SO₄, concentrated and dried to provide the title compound. ¹HNMR (400 MHz, dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 8.52-8.58 (m, 2H),8.04 (d, 1H), 7.79 (dd, 1H), 7.53 (d, 1H), 7.47-7.52 (m, 2H), 7.30-7.37(m, 2H), 7.07 (d, 1H), 7.01-7.06 (m, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H),6.19 (d, 1H), 4.25 (s, 1H), 3.25-3.32 (m, 4H), 3.07 (s, 4H), 2.75 (s,2H), 2.09-2.24 (m, 6H), 1.95 (s, 2H), 1.50-1.73 (m, 5H), 1.28-1.43 (m,4H), 1.06-1.18 (m, 5H), 0.92 (s, 6H).

Example 3384-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 338A methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoromethanesulfonic anhydride (40 mL) was added. Thereaction mixture was warmed to room temperature and stirred for 24hours. The organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated to give the product.

Example 338B methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 338A (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether (4×200 mL) was added and the mixturewas filtered. The combined ether solution was concentrated to give theproduct.

Example 338C (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 338B (53.8 g) and ether (400 mL),was added methanol (25 mL) slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N aqueousHCl with ice-cooling. The mixture was diluted with water and extractedwith ether (3×100 mL). The extracts were dried (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with0-30% ethyl acetate/hexanes.

Example 338D tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Mesyl Chloride (7.5 mL) was added via syringe to EXAMPLE 338C (29.3 g)and triethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C., and the mixturewas stirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was addedand the mixture was stirred at room temperature for 24 hours. Thesuspension was washed with brine, dried, (Na₂SO₄), filtered, andconcentrated. The crude product was chromatographed on silica gel with10-20% ethyl acetate/hexanes.

Example 338E1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

EXAMPLE 338D (1 g) was stirred in dichloromethane (10 mL),trifluoroacetic acid (10 mL), and triethylsilane (1 mL) for 1 hour. Themixture was concentrated, taken up in a mixture of dichloromethane (100mL) and saturated aqueous Na₂CO₃ solution (20 mL) and stirred for 10minutes. The layers were separated, and the organic layer was dried overNa₂SO₄, filtered, and concentrated to give the product.

Example 338F 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) intetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide intetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl(triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirredat room temperature for 24 hours. The reaction was diluted with ether,and the resulting solution was washed twice with water. The extractswere dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 10% ethyl acetate/hexanes.

Example 338G 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

To a mixture of EXAMPLE 338F (24.3 g) in tetrahydrofuran (500 mL) at−78° C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate(11.5 mL) was added, and the mixture was allowed to warm to roomtemperature over 1 hour. The reaction was poured into water, extractedthree times with ethyl acetate, and the combined extracts were washedwith brine and concentrated. The crude product was taken up intetrahydrofuran (200 mL) at 0° C., and 1M aqueous NaOH (69 mL) wasadded, followed by 30% aqueous H₂O₂ (8.43 mL), and the solution wasstirred for 1 hour. Na₂S₂O₃ (10 g) was added, and the pH was adjusted to4-5 with concentrated HCl and solid NaH₂PO₄. The solution was extractedtwice with ethyl acetate, and the combined extracts were washed withbrine, dried (Na₂SO₄), filtered, and concentrated. The crude product waschromatographed on silica gel with 5-25% ethyl acetate/hexanes.

Example 338H methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate

A mixture of EXAMPLE 338G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The crude product waschromatographed on silica gel with 2-50% ethyl acetate/hexanes.

Example 338I methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of EXAMPLE 338H (1.55 g), EXAMPLE 338E (2.42 g), and HK₂PO₄(1.42 g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24hours. The reaction was cooled, diluted with ether (400 mL), and washedthree times with 1M aqueous NaOH, and brine, and concentrated. The crudeproduct was chromatographed on silica gel with 10-50% ethylacetate/hexanes.

Example 338J2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

EXAMPLE 338I (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50° C.was stirred for 24 hours. The reaction was cooled, added to NaH₂PO₄solution, and extracted three times with ethyl acetate. The combinedextracts were washed with brine, and concentrated to give the pureproduct.

Example 338K tert-butyl (4-hydroxy-4-methylcyclohexyl)methylcarbamate

To a vigorous stirring solution of tert-butyl(4-oxocyclohexyl)methylcarbamate (1.7 g) in tetrahydrofuran (40 mL) at−78° C. was dropwise added 1.6 M methyllithium (14.02 mL) in ether.After completion of the addition, the mixture was stirred at −78° C. for1.2 hours and poured into a cold NH₄Cl aqueous solution. The resultingmixture was extracted with dichloromethane (100 ml, three times) and theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was dissolved in dichloromethane and loaded onto an Analogixpurification system, and it was eluted with 0-50% ethyl acetate indichloromethane to provide the title compound.

Example 338L 4-(aminomethyl)-1-methylcyclohexanol

EXAMPLE 338K (1.3 g) in dichloromethane (5 mL) at 0° C. was treated withtrifluoroacetic acid (2.1 mL) and a few drops of water for 1 hour. Thereaction mixture was concentrated and the residue was directly used fornext step.

Example 338M4-((cis-4-hydroxy-4-methylcyclohexyl)methylamino)-3-nitrobenzenesulfonamide

EXAMPLE 338L (732 mg) and 4-fluoro-3-nitrobenzenesulfonamide (1.1 g) intetrahydrofuran (15 mL) was treated with triethylamine overnight. Thereaction mixture, was concentrated and the residue was purified by areverse phase chromatography, eluting with 30%-50% acetonitrile in 0.1%trifluoroacetic acid water solution to isolate the title compound.

Example 338N4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A mixture of EXAMPLE 338J (144 mg), EXAMPLE 338M (95 mg), N,N-dimethylpyridin-4-amine (123 mg) andN¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (62.7 mg) in dichloromethane (7 ml) was stirred overnightand concentrated. The residue was purified by reverse chromatography,eluted with 40%-70% acetonitrile in 0.1% TFA water. The desiredfractions were concentrated, neutralized with NaHCO₃ and extracted withdichloromethane. The organic layer was dried over Na₂SO₄, filtered,concentrated and dried to provide the title compound. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.38 (s, 1H), 8.59 (t, 1H), 8.55(d, 1H), 8.04 (d, 1H), 7.79 (dd, 1H), 7.54 (d, 1H), 7.46-7.52 (m, 2H),7.30-7.38 (m, 2H), 7.00-7.10 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19(d, 1H), 3.95 (s, 1H), 3.25 (t, 4H), 3.07 (s, 4H), 2.75 (s, 2H),2.10-2.26 (m, 6H), 1.95 (s, 2H), 1.29-1.62 (m, 8H), 1.16-1.30 (m, 2H),1.08 (s, 3H), 0.92 (s, 6H).

Example 339N-[(5-chloro-6-{[(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 339A (1R,4S)-methylspiro[bicyclo[2.2.1]heptane-2,2′-[1,3]dioxolane]-5-carboxylate

A reaction mixture of 1,4-dioxaspiro[4.4]non-6-ene (5 g), methylacrylate (10.24 g), and hydroquinone (0.13 g) was heated at 100° C. inacetonitrile (12 mL) for three days. After cooling, the solvent wasremoved, and residue was purified by flash chromatography on silica geleluting with 4:1 hexane/ethyl acetate to provide the title compound as amixture of two isomers.

Example 339B(1R,4S)-spiro[bicyclo[2.2.1]heptane-2,2′-[1,3]dioxolane]-5-ylmethanol

EXAMPLE 339A (1.0 g) in tetrahydrofuran was cooled to 0° C. To thissolution was added 1.0 N lithium aluminum hydride (2.8 mL) dropwise. Thereaction mixture was stirred for 2 hours. Water (0.4 mL) was addedfollowed by 2 N aqueous NaOH (0.2 mL). The solid was filtered off, andthe filtrate was concentrated. Toluene was added, and it was thendistilled to remove any trace amount of water. The title compound wasused for the next reaction without further purification.

Example 339C5-chloro-6-(((1S,2R,4R)-5-oxobicyclo[2.2.1]heptan-2-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 339B for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for EXAMPLE 36A inEXAMPLE 36B. The two stereoisomers at the 5 position were isolated byreverse phase Gilson Prep HPLC system with a Phenomenex prep column(Luna, 5μ, C18(2), 250×21.20 mm, 5 Å) eluting with 20-80% acetonitrle inwater with 0.1% trifluoroacetic acid. The desired fractions werecollected, and the solvents were removed under reduced vacuum at 60° C.During this process, a lot of solid formed. It was then partitionedbetween water and ethyl acetate. The organic layer was separated, andthe aqueous layer was extracted with additional ethyl acetate. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated to give the title compound.

Example 339D5-chloro-6-(((1S,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]heptan-2-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 339C (0.44 g) in tetrahydrofuran (15 mL) was treated with 3.0 Mmethylmagnesium bromide (5.3 mL) at 0° C. The solution was stirred for16 hours. The reaction mixture was then partitioned between ethylacetate and 0.05 N aqueous HCl (20 mL). The organic layer was separated,and the aqueous layer was extracted with additional ethyl acetate threetimes. The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashcolumn chromatography on silica gel using 10-50% ethyl acetate inhexanes to provide the title compound.

Example 339EN-[(5-chloro-6-{[(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 339D for EXAMPLE11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.66 (s,1H), 8.50 (s, 1H), 8.16 (s, 1H), 8.02 (d, 1H), 7.49-7.55 (m, 3H), 7.35(d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.38 (dd, 1H), 6.20 (s, 1H),4.40-4.48 (m, 2H), 4.31 (s, 1H), 3.09 (s, 4H), 2.83 (s, 2H), 2.15-2.33(m, 7H), 1.96 (s, 2H), 1.87 (d, 1H), 1.65-1.69 (m, 1H), 1.54-1.56 (m,2H), 1.36-1.47 (m, 6H), 1.26-1.30 (m, 1H), 1.19 (s, 3H), 0.93 (s, 6H).

Example 3404-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 340A4-(1,4-dioxaspiro[4.5]decan-8-ylamino)-3-nitrobenzenesulfonamide

To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.4 g) intetrahydrofuran (30 mL) was added 1,4-dioxaspiro[4.5]decan-8-amine (1.0g) and diisopropylethylamine (5 mL). The mixture was stirred overnight.The mixture was diluted with ethyl acetate (300 mL) and washed withwater, brine and dried over Na₂SO₄. Filtration and evaporation of thesolvent gave the title compound.

Example 340BN-(4-(1,4-dioxaspiro[4.5]decan-8-ylamino)-3-nitrophenylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

To a solution of EXAMPLE 3J (617 mg) and EXAMPLE 340A (386 mg) indichloromethane (10 mL) was added1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (288 mg)and 4-(dimethylamino)pyridine (183 mg). The mixture was stirredovernight. The mixture was diluted with dichloromethane (300 mL) andwashed with aqueous NaHCO₃, water, brine and dried over Na₂SO₄.Filtration and evaporation of the solvent gave the title compound.

Example 340C2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(4-oxocyclohexylamino)phenylsulfonyl)benzamide

To a solution of EXAMPLE 340B (386 mg) in acetone (10 mL) and water (5mL) was added para-toluenesulfonic acid monohydrate (50 mg). The mixturewas stirred at 120° C. in a Biotage Initiator microwave reactor for 30minutes. The mixture was diluted with dichloromethane (300 mL) andwashed with aqueous NaHCO₃, water, brine and dried over Na₂SO₄.Filtration and evaporation of the solvent gave the title compound.

Example 340D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a solution of EXAMPLE 340C (240 mg) and3-(cyclopropylamino)propanenitrile (62 mg) in tetrahydrofuran (10 mL)was added acetic acid (2 mL) and MP-cyanoborohydride (300 mg, 2.15mmol/g). The mixture was stirred overnight. The mixture was filtered andconcentrated under vacuum and the residue was dissolved indimethylsulfoxide/methanol (1:1, 10 mL) and loaded on Gilson, C18(100A)250×121.2 mm (10 micron), with 30% acetonitrile to 65% acetonitrile over40 minutes. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 8.55(dd, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.49 (m, 3H), 7.34(d, 2H), 7.11 (m, 1H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.38 (d, 1H), 6.19(d, 1H), 4.01 (m, 1H), 3.56 (m, 1H), 3.06 (m, 4H), 2.88 (t, 2H), 2.65(m, 6H), 2.19 (m, 6H), 2.00 (m, 7H), 1.51 (m, 6H), 0.92 (s, 6H), 0.42(m, 4H).

Example 341N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 341A ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate

To a solution of ethyl 4-oxocyclohexanecarboxylate (31.8 g) in toluene(100 mL) was added ethylene glycol (36.5 mL) and p-toluenesulfonic acidmonohydrate (0.426 g). The two phase mixture was stirred rapidly atambient temperature for 72 hours. The reaction was diluted with water(900 mL) and extracted with ether (900 mL). The organic layer was washedwith saturated sodium bicarbonate solution and brine, and then driedover anhydrous sodium sulfate. After filtration, the title compound wasobtained by concentration under high vacuum.

Example 341B 1,4-dioxaspiro[4.5]decan-8-ylmethanol

To a suspension of lithium aluminum hydride (8.19 g) in tetrahydrofuran(400 mL) was added dropwise a solution of EXAMPLE 341A (37.8 g) intetrahydrofuran (75 mL). The mixture was then heated at reflux for 2hours. The reaction mixture was cooled in an ice bath and quenched veryslowly with water (8 mL). Then added sequentially were 4N sodiumhydroxide (8 mL), ether (200 mL), water (24 mL), ether (500 mL) andanhydrous sodium sulfate (250 g). The resulting mixture was stirredrapidly for 2 hours and was filtered. The title compound was isolated byconcentration of the filtrate.

Example 341C 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane

To a suspension of sodium hydride (60% oil dispersion, 8.86 g) intetrahydrofuran (170 mL) was added a solution of EXAMPLE 341B (30.52 g)in tetrahydrofuran (100 mL). This mixture was stirred for 30 minutes andbenzyl bromide (24 mL) was added. After stirring for 72 hours, thereaction was quenched with saturated ammonium chloride solution (400 mL)and diluted with ether (500 mL). The layers were separated and theaqueous layer was extracted with ether (2×150 mL). The combined organicswere dried over sodium sulfate, filtered and concentrated. The crudeproduct was purified on silica gel eluting with a 0, 10, 15, 75% ethylacetate in hexanes step gradient to provide the title compound.

Example 341D 4-(benzyloxymethyl)cyclohexanone

To a solution of EXAMPLE 341C (43.02 g) in dioxane (500 mL) was addedwater (125 mL) and 2M hydrochloric acid (90 mL). The mixture was heatedat 85° C. for 18 hours. Upon cooling, the reaction mixture was dilutedwith brine (1500 ml), saturated sodium bicarbonate solution (300 mL) andether (1000 mL). The organic layer was dried over sodium sulfate,filtered and concentrated. The crude product was purified on silica geleluting with a 5-50% ethyl acetate in hexanes step gradient to providethe title compound.

Example 341E trans-4-(benzyloxymethyl)-1-methylcyclohexanol

To 2,6-di-t-butyl-4-methylphenol (83.4 g) in toluene (1100 mL) was added2.0M (in hexanes) trimethylaluminum (95 mL) somewhat carefully tocontrol methane evolution and a small exotherm. The reaction mixture wasstirred at ambient temperature under N₂ for 75 minutes and was thencooled to −77° C. A solution of EXAMPLE 341D (14 g) in toluene (15 mL)was added dropwise, keeping the temperature below −74° C. Methyllithium(1.6M in diethyl ether, 120 mL) was then added dropwise, keeping thetemperature below −65° C. The resulting mixture was stirred at −77° C.under N₂ for 2 hours. The reaction mixture was then poured into 1Naqueous HCl (1600 mL), rinsing the flask with toluene. The organic layerwas washed with brine and the combined aqueous layers were extractedwith diethyl ether. The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The concentrate was chromatographed on 650 gof spherical silica gel using 2.5 L of 80/20 hexanes/ethyl acetate, then3.0 L of 75/25 hexanes/ethyl acetate, and finally 4.0 L of 70/30hexanes/ethyl acetate as the eluents to provide the title compound.

Example 341F Trans-4-(hydroxymethyl)-1-methylcyclohexanol

EXAMPLE 341E (12.6 g) and ethanol (120 ml) were added to 20% Pd(OH)₂/C,wet (1.260 g) in a 500 mL SS pressure bottle. The reaction mixture wasstirred at ambient temperature under 30 psi hydrogen gas. Hydrogenuptake ceased at 5 minutes. The mixture was filtered through a nylonmembrane rinsing with ethanol. The filtrate was concentrated and thenazeotroped with toluene (100 mL) to remove any remaining ethanol. Theconcentrate was dried under high vacuum for 40 minutes to provide thetitle compound.

Example 341G5-chloro-6-((trans-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 40A for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 341F for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 341HN-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 328E for EXAMPLE3J and EXAMPLE 341G for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (500 MHz,pyridine-d₅) δ 13.09 (s, 1H), 9.18 (d, 1H), 8.74 (d, 1H), 8.41 (d, 1H),8.09 (d, 1H), 7.67 (m, 2H), 7.42 (m, 2H), 7.09 (m, 2H), 6.74 (dd, 1H),6.52 (dd, 1H), 6.49 (d, 1H), 4.29 (d, 2H), 3.05 (m, 4H), 2.80 (s, 2H),2.37 (t, 2H), 2.15 (m, 4H), 2.11 (s, 2H), 1.89 (m, 6H), 1.75 (m, 2H),1.45 (t, 2H), 1.41 (s, 3H), 1.32 (m, 2H), 0.37 (m, 4H).

Example 3424-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 342A methyl5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate

To a 50 ml pressure bottle were placed methylimidazo[1,2-a]pyridine-6-carboxylate (0.26 g), acetic acid (10 ml), andwet 5% palladium on carbon (0.052 g). The reaction mixture was stirredfor 16 hours at 30 psi and 50° C. The solid was filtered off, and thefiltrate was concentrated. The residue was taken up in ethyl acetate. Itwas then washed with saturated sodium bicarbonate, brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashcolumn chromatography on silica gel using 10-100% ethyl acetate inhexanes to provide the title compound.

Example 342B (5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)methanol

The title compound was prepared by substituting EXAMPLE 342A for EXAMPLE339A in EXAMPLE 339B.

Example 342C5-chloro-6-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 342B for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for EXAMPLE 36A inEXAMPLE 36B.

Example 342D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 342C for EXAMPLE11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.54 (s,1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.58 (d, 1H), 7.41-7.44(m, 2H), 7.2-7.36 (m, 4H), 7.05 (d, 2H), 6.63 (dd, 1H), 6.32 (dd, 1H),6.24 (d, 1H), 4.42-4.51 (m, 1H), 4.37-4.40 (m, 1H), 4.29 (dd, 1H), 3.91(dd, 1H), 3.03 (s, 4H), 2.90-2.95 (m, 2H), 2.77 (s, 2H), 2.51-2.52 (m,1H), 2.07-2.23 (m, 7H), 1.96 (s, 2H), 1.76-1.82 (m, 1H), 1.65-1.69 (m,2H), 1.54-1.56 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 343N-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 343A5-chloro-6-(((1S,2S,4R)-5-oxobicyclo[2.2.1]heptan-2-yl)methoxy)pyridine-3-sulfonamide

The title compound was isolated as another isomer in EXAMPLE 339C.

Example 343B5-chloro-6-(((1S,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]heptan-2-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 343A for EXAMPLE339B in EXAMPLE 339C.

Example 343CN-[(5-chloro-6-{[(1R,2S,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 343B for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.67 (s,1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.49-7.55 (m, 3H), 7.35(d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.20 (d, 1H), 4.27(s, 1H), 4.11-4.19 (m, 2H), 3.11 (s, 4H), 2.87 (s, 2H), 1.96-2.23 (m,10H), 1.88 (d, 1H), 1.50 (dd, 1H), 1.33-1.44 (m, 2H), 1.13-1.19 (m, 4H),0.88-0.93 (m, 8H).

Example 3444-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 344A4-((cis-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrobenzenesulfonamide

EXAMPLE 347A (732 mg) and 4-fluoro-3-nitrobenzenesulfonamide (1.2 g) intetrahydrofuran (40 mL) were treated with 60% sodium hydride (1.6 g) for3 days. The reaction was quenched with water. The resulting mixture wasneutralized with diluted aqueous HCl, and extracted with ethyl acetate.The organic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by a reverse phase chromatography, eluting with30-50% CH₃CN in 0.1% trifluoroacetic acid water to provide the titlecompound as a single enantiomer.

Example 344B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 344A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 8.34 (d, 1H), 8.04 (m, 2H), 7.52(m, 3H), 7.40 (d, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.40(m, 1H), 6.20 (d, 1H), 4.02 (d, 2H), 3.96 (s, 1H), 3.10 (br s, 4H), 2.85(m, 2H), 2.29 (m, 3H), 2.15 (t, 2H), 1.96 (br s, 2H), 1.68 (m, 1H), 1.55(m, 4H), 1.42 (m, 4H), 1.27 (m, 2H), 1.10 (s, 3H), 0.92 (s, 6H).

Example 345N-[(5-chloro-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 328E for EXAMPLE3J and EXAMPLE 277O for EXAMPLE 11B in EXAMPLE 11D. ¹H NMR (500 MHz,pyridine-d₅) δ 13.07 (s, 1H), 9.13 (d, 1H), 8.41 (d, 1H), 8.09 (d, 1H),7.68 (t, 1H), 7.66 (d, 1H), 7.42 (m, 2H), 7.09 (m, 2H), 6.75 (dd, 1H),6.51 (m, 2H), 4.64 (d, 4H), 4.53 (d, 2H), 3.39 (m, 1H), 3.06 (m, 4H),2.81 (s, 2H), 2.51 (m, 2H), 2.37 (m, 2H), 2.12 (m, 10H), 1.90 (m, 2H),1.45 (t, 2H), 0.38 (s, 4H).

Example 3464-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting 3,3-difluoropyrrolidinehydrochloride for 3-(cyclopropylamino)propanenitrile in EXAMPLE 340D. ¹HNMR (300 MHz, dimethylsulfoxide-d₆) δ 11.68 (s, 1H), 11.38 (m, 1H), 8.55(m, 1H), 8.36 (d, 1H), 8.03 (d, 1H), 7.80 (m, 1H), 7.50 (m, 3H), 7.34(d, 2H), 7.13 (d, 1H), 7.04 (d, 2H), 6.83 (m, 1H), 6.68 (m, 1H), 6.38(d, 1H), 6.19 (s, 1H), 4.02 (s, 1H), 3.83 (m, 1H), 3.06 (m, 4H), 2.96(m, 2H), 2.73 (m, 4H), 2.26 (m, 8H), 1.97 (m, 4H), 1.68 (m, 4H), 1.37(m, 2H), 0.92 (s, 6H).

Example 347N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 347A 4-(hydroxymethyl)-1-methylcyclohexanol

4-(Hydroxymethyl)cyclohexanone (800 mg) in tetrahydrofuran (15 mL) wastreated with 3 M methylmagnesium chloride in tetrahydrofuran (6.24 mL)at 0° C. The reaction was warmed to room temperature over 2 hours andquenched with methanol and water. The resulting mixture was concentratedand the residue was suspended in ethyl acetate. The precipitates werefiltered off and the filtrate was concentrated. The residue was purifiedby chromatography, eluting with 0-100% ethyl acetate in hexane toprovide the title compound.

Example 347B5-chloro-6-((trans-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3-sulfonamide

EXAMPLE 347A (970 mg) and EXAMPLE 40A (1.6 g) in N,N-dimethylformamide(8 mL) were treated with sodium hydride (1.8 g, 60%) at room temperaturefor 2 days. The reaction was quenched with water. The resulting mixturewas neutralized with diluted aqueous HCl, and extracted with ethylacetate. The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by a reverse phasechromatography, eluting with 30-45% acetonitrile in 0.1% trifluoroaceticacid water to isolate the title compound.

Example 347C5-chloro-6-((cis-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3-sulfonamide

The title compound was prepared and isolated as described in Example347B.

Example 347DN-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 347B in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 8.51 (d, 1H), 8.18 (d, 1H), 8.03(d, 1H), 7.48-7.56 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H),6.39 (dd, 1H), 6.21 (d, 1H), 4.17-4.34 (m, 3H), 3.11 (s, 4H), 2.89 (s,2H), 2.24-2.42 (m, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.66-1.82 (m, 3H),1.55 (d, 2H), 1.31-1.44 (m, 4H), 1.12-1.27 (m, 2H), 1.10 (s, 3H), 0.93(s, 6H).

Example 348N-({5-chloro-6-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 347C in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 8.51 (d, 1H), 8.18 (d, 1H), 8.03(d, 1H), 7.47-7.58 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2 H), 6.68 (dd, 1H),6.39 (dd, 1H), 6.21 (d, 1H), 4.21 (d, 2H), 3.95 (s, 1H), 3.11 (s, 4H),2.89 (s, 2H), 2.33 (d, 4H), 2.15 (s, 2H), 1.96 (s, 2H), 1.63-1.77 (m,1H), 1.48-1.60 (m, 4H), 1.35-1.48 (m, 4H), 1.20-1.33 (m, 2H), 1.09 (s,3H), 0.93 (s, 6H).

Example 3494-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2,2-difluorocyclopropyl)amino]cyclohexyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting2,2-difluorocyclopropanamine hydrochloride for3-(cyclopropylamino)propanenitrile in EXAMPLE 340D. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.60 (s, 1H), 8.47 (m, 2H), 8.12 (m, 1H), 7.98(m, 1H), 7.72 (m, 2H), 7.47 (m, 3H), 7.34 (m, 3H), 7.05 (m, 3H), 6.65(dd, 1H), 6.35 (m, 1H), 6.22 (d, 1H), 3.54 (m, 2H), 3.08 (m, 4H), 2.74(m, 4H), 2.25 (m, 4H), 2.01 (m, 4H), 1.38 (m, 4H), 0.92 (s, 6H).

Example 350N-({5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 350A ethylspiro[benzo[d][1,3]dioxole-2,1′-cyclohexane]-4′-carboxylate

To a solution of ethyl 4-oxocyclohexanecarboxylate (22.75 g) andpyrocatechol (14.75 g) in toluene (200 mL) was added catalytic amount ofpara-toluenesulfonic acid monohydrate and the mixture was stirred underreflux and a Dean-Stark trap overnight. The mixture was diluted withdiethyl ether (600 mL) and washed with aqueous NaHCO₃, water and brine.After drying over Na₂SO₄, the mixture was filtered and the solvent wasevaporated under vacuum to provide the title compound.

Example 350B ethyl4′-fluorospiro[benzo[d][1,3]dioxole-2,1′-cyclohexane]-4′-carboxylate

A solution of EXAMPLE 350A (5.25 g) in tetrahydrofuran (40 mL) was addeddropwise to a solution of lithium diisopropylamide (12 mL, 2.0M intetrahydrofuran/heptane/ethylbenzene) at 0° C. The solution was stirredat 0° C. for 30 minutes, and then was transferred by cannula to apre-cooled (0° C.) stirring solution of (7.89 g) in dry tetrahydrofuran(20 mL). The reaction mixture was stirred at 0° C. for 30 minutes, andthen at 20° C. for 18 hours. The reaction mixture was poured overaqueous NH₄Cl and extracted with diethyl ether (3×200 mL). The combinedorganic layers were washed with water, brine and dried over Na₂SO₄.Filtration and evaporation of the solvent gave the crude product.

Example 350C(4′-fluorospiro[benzo[d][1,3]dioxole-2,1′-cyclohexane]-4′-yl)methanol

To a solution of EXAMPLE 350B (23 g) in tetrahydrofuran (150 mL) wasadded lithium aluminum hydride (3.11 g). The mixture was stirredovernight. Aqueous 2N NaOH solution was added dropwise to the reactionmixture. The mixture was then diluted with ethyl acetate (600 mL) andwashed with water, brine and dried over Na₂SO₄. Filtration andevaporation of the solvent gave the crude product which was loaded on a600 g ANALOGIX column and eluted with 10% to 20% ethyl acetate in hexaneto provide the title compound.

Example 350D5-chloro-6-((4′-fluorospiro[benzo[d][1,3]dioxole-2,1′-cyclohexane]-4′-yl)methoxy)pyridine-3-sulfonamide

To a solution of EXAMPLE 350C (89 mg) in N,N-dimethylformamide (3 mL)was added NaH (65% in mineral oil, 36 mg). The mixture was stirred for30 minutes, and then 5, 6-dichloropyridine-3-sulfonamide (85 mg) wasadded. The mixture was stirred overnight. The mixture was poured overaqueous NH₄Cl and extracted with ethyl acetate (100 mL). The combinedorganic layers were washed with water, brine and dried over Na₂SO₄.After filtration and evaporation of the solvent, the residue was loadedon a silica gel cartridge and eluted with 30% ethyl acetate in hexane toprovide the title compound.

Example 350E5-chloro-6-((1-fluoro-4-oxocyclohexyl)methoxy)pyridine-3-sulfonamide

To a solution of EXAMPLE 350D (1.6 g) and pyridinium p-toluenesulfonate(1.2 g) in acetone (10 mL) was added water (2 mL) and the mixture wasstirred under microwave irradiation at 100° C. for 10 minutes. Themixture was diluted with dichloromethane (300 mL) and washed withaqueous NaHCO₃, water, brine and dried over Na₂SO₄. Filtration andevaporation of the solvent gave the title compound.

Example 350F5-chloro-6-((cis-1-fluoro-4-hydroxycyclohexyl)methoxy)pyridine-3-sulfonamide

To a solution of EXAMPLE 350E (336 mg) in tetrahydrofuran (10 mL) wasadded NaBH₄ (75 mg). The mixture was stirred for 45 minutes. The mixturewas diluted with ethyl acetate (300 mL) and washed with 2N aqueous NaOH,water, and brine. After drying over Na₂SO₄, the mixture was filtered andthe solvent was evaporated to give the crude product.

Example 350GN-({5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 350F for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.63 (s, 1H), 8.48 (s, 1H), 8.18 (s, 1H), 8.01(d, 1H), 7.50 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.37(dd, 1H), 6.21 (d, 1H), 4.62 (d, 1H), 4.47 (s, 1H), 4.40 (s, 1H), 3.46(m, 1H), 3.06 (m, 4H), 2.88 (m, 1H), 2.25 (m, 6H), 1.99 (m, 4H), 1.58(m, 8H), 0.93 (s, 6H).

Example 3514-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(2-oxaspiro[3.5]non-7-ylmethoxy)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 351A diethyl 1,4-dioxaspiro[4.5]decane-8,8-dicarboxylate

A 500 mL round-bottomed flask was charged with diisopropylamine (16 mL)and tetrahydrofuran (311 mL). The solution was cooled to −78° C. underN₂ and n-BuLi (2.5 M in hexanes, 44.8 mL)) was added. The reaction wasstirred for 30 minutes at −78° C. and ethyl1,4-dioxaspiro[4.5]decane-8-carboxylate (20 g) was added as atetrahydrofuran solution (ca. 10 mL). The solution was stirred at −78°C. for 1 hour and ethyl chloroformate (9 mL) was added neat. Afterstirring at −78° C. for 10 minutes, the reaction was warmed to roomtemperature over 2 hours. The reaction was quenched with saturatedaqueous NH₄Cl and was diluted with diethyl ether. The layers wereseparated, the aqueous layer was extracted with diethyl ether and thecombined organics were dried (Na₂SO₄), filtered and concentrated byrotary evaporation. The residue was purified by regular phase flashcolumn chromatography (Analogix, 0-65% hexanes/ethyl acetate).

Example 351B 1,4-dioxaspiro[4.5]decane-8,8-diyldimethanol

To a 1 L round-bottomed flask was added EXAMPLE 351A (26.6 g) andtetrahydrofuran (310 mL) to give a colorless solution. The solution wascooled to 0° C. and lithium aluminum hydride (2M in tetrahydrofuran, 62mL) was added via syringe. The reaction was allowed to warm to roomtemperature and stirred overnight. The mixture was cooled back down to0° C. and quenched slowly with 4.7 mL water, 4.7 mL 10% aqueous NaOH and14 mL water. The mixture was allowed to stir until salts were formed andwas then filtered through a Supelco 90 mm silica gel Buchner funnel. Thefiltrate was concentrated by rotary evaporation and the residue waspurified by regular phase flash column chromatography (Analogix, 0-80%hexanes/ethyl acetate).

Example 351C 2,8,11-trioxa-dispiro[3.2.4]tridecane

To a 1 L round-bottomed flask was added EXAMPLE 351B (13 g) intetrahydrofuran (321 mL). The solution was cooled to −78° C. under N₂and n-BuLi (25.7 mL) was added dropwise via syringe. After addition wascomplete, the mixture stirred for 30 minutes and a tetrahydrofuransolution of 4-toluenesulfonyl chloride (12.25 g) was added via additionfunnel. The reaction was allowed to stir overnight, and gradually warmto room temperature. The reaction mixture was cooled to −78° C. andn-BuLi (25.7 mL) was added. The mixture was warmed to room temperatureand stirred for 3 hours. The reaction was quenched with sat aqueousNH₄Cl and diluted with diethyl ether. The layers were separated, theaqueous layers extracted with diethyl ether and the combined organicswere dried (Na₂SO₄), filtered and concentrated by rotary evaporation.The residue was purified by regular phase flash column chromatography(Analogix, 0-20% acetone/hexanes).

Example 351D 2-oxaspiro[3.5]nonan-7-one

To a 500 mL round-bottomed flask was added EXAMPLE 351C (11 g) in 80%aqueous acetic acid (200 mL). The reaction was heated to 65° C. andstirred for about 4 hours. Most of the acetic acid and water wereremoved by rotary evaporation and the residue was purified by regularphase flash column chromatography (Analogix, 0-65% hexanes/ethylacetate).

Example 351E 7-methylene-2-oxaspiro[3.5]nonane

To a 250 mL round-bottomed flask was added methyltriphenylphosphoniumiodide (4.33 g) in tetrahydrofuran (35.7 mL) to give a suspension. Thesuspension was cooled to −15° C. n-BuLi (2.5 M in hexanes, 4.28 mL) wasadded dropwise and the mixture was stirred at −15° C. for 40 minutes andEXAMPLE 351D (1 g) was added as a tetrahydrofuran (ca. 5 mL) solution.The mixture was stirred at −15° C. for about 15 minutes and warmed toroom temperature. After 1.5 hours, the reaction was complete and wasquenched with saturated aqueous NH₄Cl and diluted with diethyl ether.The layers were separated and the aqueous layer was extracted (2×) withdiethyl ether. The combined organics were washed with brine, dried(Na₂SO₄), filtered and concentrated by rotary evaporation. The residuewas purified by regular phase chromatography (Analogix, 80 g Gracesilica gel column, 0-50% hexanes/ethyl acetate).

Example 351F 2-oxaspiro[3.5]nonan-7-ylmethanol

To a 25 mL round-bottomed flask was added EXAMPLE 351E (568 mg) andEXAMPLE 351F tetrahydrofuran (4.11 mL) to give a colorless solution.9-Borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 24.7 mL) was addedand the reaction was allowed to stir for 2 hours at room temperature.Ethanol (11 mL) was added followed by aqueous NaOH (5M, 4.11 mL) andthen hydrogen peroxide (2.1 mL) was added. The reaction was heated at50° C. for 2 hours. The mixture was concentrated by rotary evaporation,and diluted with water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate (3×) and the combined organics were dried(Na₂SO₄), filtered and concentrated by rotary evaporation. The residuewas purified by regular phase flash column chromatography (Analogix, 80g Grace, 0-70% hexanes/ethyl acetate).

Example 351G4-(2-oxaspiro[3.5]nonan-7-ylmethoxy)-3-nitrobenzenesulfonamide

EXAMPLE 351G was prepared substituting EXAMPLE 351F for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 351H2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-(2-oxaspiro[3.5]nonan-7-ylmethoxy)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 351G for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H) 8.34 (s, 1H) 8.03 (d, 2H)7.45-7.57 (m, 3H) 7.30-7.40 (m, 3H) 7.04 (d, 2H) 6.67 (dd, 1H) 6.39 (dd,1H) 6.17-6.23 (m, 1H) 4.29 (s, 2H) 4.20 (s, 2H) 4.00 (d, 2H) 3.08 (s,4H) 2.73-2.90 (m, 2H) 2.72 (s, 1H) 2.01-2.32 (m, 6H) 1.96 (s, 2H)1.64-1.78 (m, 4H) 1.33-1.50 (m, 6H) 0.96-1.15 (m, 2H) 0.92 (s, 6H).

Example 3524-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 352A4-((trans-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 341F for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 352B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 352A for EXAMPLE1F and EXAMPLE 3J for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 8.31 (br s, 1H), 8.01 (m, 2H),7.49 (m, 3H), 7.33 (m, 3H), 7.03 (m, 2H), 6.66 (dd, 1H), 6.37 (m, 1H),6.19 (d, 1H), 4.27 (s, 1H), 4.05 (d, 2H), 3.40 (m, 2H), 3.17 (s, 1H),3.07 (m, 3H), 2.79 (m, 1H), 2.24 (m, 3H), 2.14 (m, 2H), 1.94 (m, 2H),1.71 (m, 3H), 1.52 (m, 2H), 1.38 (m, 4H), 1.22 (m, 2H), 1.09 (s, 3H),0.91 (s, 6H).

Example 3534-(4-{[2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 353A 1,4-dioxaspiro[4.5]decane-8,8-diylbis(methylene)bis(4-methylbenzenesulfonate)

To a 500 mL round-bottomed flask was added EXAMPLE 351B (10 g) anddichloromethane (165 mL) to give a colorless solution. Triethylamine(24.1 mL) and toluene-2-sulfonyl chloride (19.8 g) were added followedby 4-dimethylaminopyridine (0.604 g). The reaction was refluxedovernight. Saturated aqueous NH₄Cl was added followed by dilution withwater and additional dichloromethane. The aqueous layer was extractedwith dichloromethane (2×) and the combined organics were dried (MgSO₄),filtered and concentrated by rotary evaporation. The residue waspurified by regular phase flash column chromatography (Analogix, 0-55%hexanes/ethyl acetate).

Example 353B 8,8-bis(fluoromethyl)-1,4-dioxaspiro[4.5]decane

To a 500 mL round-bottomed flask was added EXAMPLE 353A (20 g).tetra-n-Butylammonium fluoride (1M in tetrahydrofuran, 200 mL) was addedand the resulting solution was refluxed for 6 days. The reaction wascooled, diluted with diethyl ether and washed with water (3×). Theorganics were dried (Na₂SO₄), filtered and concentrated by rotaryevaporation. The residue was purified by regular phase flash columnchromatography (Analogix, 0-30% hexanes/ethyl acetate).

Example 353C 4,4-bis(fluoromethyl)cyclohexanone

To a 250 mL round bottom flask was added EXAMPLE 353B (1.1 g) and 80%aqueous acetic acid (50 mL). The reaction was heated at 65° C. for 3hours, cooled and concentrated by rotary evaporation to remove most ofthe acetic acid and water. The residue was purified by regular phaseflash column chromatography (Analogix, 0-50% hexanes/ethyl acetate).

Example 353D 2-chloro-5,5-bis(fluoromethyl)cyclohex-1-enecarbaldehyde

To a 100 mL pear flask was added N,N-dimethylformamide (498 μl) anddichloromethane (8.9 mL) to give a colorless solution. The solution wascooled to 0° C. and POCl₃ (550 μl) was added dropwise and then themixture was warmed to room temperature for 30 minutes. In the meantime,to a 100 mL pear shaped flask was added EXAMPLE 353C (870 mg, 5.36 mmol)in dichloromethane (8941 μl) to give a colorless solution. The Vilsmeierreagent was then taken up in a syringe and added dropwise to the4,4-bis(fluoromethyl)cyclohexanone (870 mg) solution at roomtemperature. The resulting solution was stirred overnight. The reactionwas poured into saturated aqueous NaHCO₃ and ice, warmed to roomtemperature and extracted with dichloromethane (3×30 mL). The organicswere combined, dried over MgSO₄, filtered and concentrated by rotaryevaporation. The residue was purified by regular phase flash columnchromatography (Analogix (0-60% hexanes/ethyl acetate).

Example 353E2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-enecarbaldehyde

To a 20 mL vial was added EXAMPLE 353D (460 mg), 4-chlorophenylboronicacid (414 mg), potassium carbonate (762 mg), tetrabutylammonium bromide(711 mg), palladium (II) acetate (14.85 mg) and water (2450 μl) to givea suspension which was degassed with N₂ for 2 minutes. The reaction wasstirred at 45° C. overnight, cooled, and poured over a Supelco silicagel Buchner funnel, washing with ethyl acetate several times. Thefiltrate was concentrated by rotary evaporation and the residue waspurified by regular phase flash column chromatography (Analogix, 0-60%hexanes/ethyl acetate).

Example 353F methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a 20 mL vial was added EXAMPLE 353E (240 mg), EXAMPLE 15F (297 mg)and dichloromethane (4.2 mL). Sodium triacetoxyborohydride (268 mg) wasadded and the reaction was stirred overnight at room temperature. Thereaction was loaded directly onto silica gel and purified by regularphase flash column chromatography (Analogix, 0-80% hexanes/ethylacetate).

Example 353G2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 353F for EXAMPLE15G in EXAMPLE 15H.

Example 353H2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-bis(fluoromethyl)cyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

EXAMPLE 353H was prepared by replacing EXAMPLE 3J with EXAMPLE 353G andEXAMPLE 11B with EXAMPLE 1F in EXAMPLE 11D. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H) 11.44 (s, 1H) 8.48-8.70 (m, 1H)8.05 (d, 2H) 7.81 (dd, 1H) 7.46-7.59 (m, 3H) 7.35 (d, 2H) 7.12 (d, 2H)6.68 (dd, 1H) 6.40 (dd, 1H) 6.16 (d, 1H) 4.39-4.49 (m, 2H) 4.23-4.35 (m,2H) 3.85 (dd, J=11.87, 2.71 Hz, 2H) 3.20-3.30 (m, 4H) 2.98-3.10 (m, 4H)2.66-2.77 (m, 2H) 2.11-2.30 (m, 6H) 2.02-2.12 (m, 3H) 1.99 (s, 1H)1.82-1.97 (m, 1H) 1.54-1.67 (m, 4H) 1.20-1.34 (m, 2H).

Example 3544-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 354A tert-butyl2-((2-nitro-4-sulfamoylphenoxy)methyl)morpholine-4-carboxylate

The title compound was prepared by substituting tert-butyl2-(hydroxymethyl)-morpholine-4-carboxylate fortetrahydro-2H-pyran-4-yl-methanol EXAMPLE 24A.

Example 354B 4-(morpholin-2-ylmethoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 354A for EXAMPLE113A in EXAMPLE 134A.

Example 354C4-((4-cyclopropylmorpholin-2-yl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 354B for EXAMPLE173A in EXAMPLE 173B.

Example 354D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-cyclopropylmorpholin-2-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 354C for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 12.98 (s, 1H),9.06 (d, 1H), 8.50 (dd, 1H), 8.41 (d, 1H), 8.09 (d, 1H), 7.66 (t, 1H),7.62 (d, 1H), 7.44 (d, 2H), 7.26 (d, 1H), 7.07 (d, 2H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 4.31 (dd, 1H), 4.22 (dd, 1H), 3.92 (m, 1H),3.83 (d, 1H), 3.56 (dt, 1H), 3.07 (m, 5H), 2.77 (s, 2H), 2.68 (d, 1H),2.35 (m, 2H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.59 (m, 1H),1.39 (t, 2H), 0.94 (s, 6H), 0.40 (m, 4H).

Example 355N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 355A5-chloro-6-((trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3-sulfonamide

To a cooled (0° C.) solution of EXAMPLE 350E (1.2 g) in tetrahydrofuran(30 mL) was added dropwise a solution of methylmagnesium bromide (5 mL,3.0M in ether). Upon addition, the reaction mixture solidified. Moretetrahydrofuran (10 mL) was added to the mixture and stirring wascontinued for 1 hour. The mixture was poured over aqueous NH₄Cl andextracted with ethyl acetate (3×150 mL). The combined organic layerswere washed with water, brine and dried over Na₂SO₄. The mixture wasfiltered and concentrated. The residue was dissolved indimethylsulfoxide/methanol (20 mL, 1:1) and loaded on loaded on Gilson,C18(100A) 250×121.2 mm (10 micron), with 30% acetonitrile to 65%acetonitrile over 40 minutes to separate the two isomers and isolate thetitle compound.

Example 355BN-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 355A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.63 (s, 1H), 8.47 (s, 1H), 8.17 (s, 1H), 7.54(d, 1H), 7.48 (m, 2H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.37(d, 1H), 6.22 (d, 1H), 4.49 (s, 1H), 4.42 (s, 1H), 4.15 (s, 1H), 3.06(m, 4H), 2.84 (m, 1H), 2.25 (m, 6H), 1.96 (s, 3H), 1.83 (m, 4H), 1.44(m, 6H), 1.14 (s, 3H), 0.93 (s, 6H).

Example 356N-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 356A5-chloro-6-((cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy)pyridine-3-sulfonamide

The title compound was prepared as described in EXAMPLE 355A.

Example 356BN-({5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 356A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.65 (s, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 8.03(d, 1H), 7.51 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.67 (dd, 1H), 6.39(dd, 1H), 6.21 (d, 1H), 4.55 (s, 1H), 4.48 (s, 1H), 4.34 (s, 1H), 3.08(m, 4H), 2.89 (d, 2H), 2.27 (m, 5H), 1.93 (m, 4H), 1.66 (m, 4H), 1.43(m, 4H), 1.11 (s, 3H), 0.93 (s, 6H).

Example 3574-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-cyano-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 357A ethyl 4-fluoro-1-(oxetan-3-yl)piperidine-4-carboxylate

To 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.000 g)was added HCl (4.0M in dioxane, 4.54 mL). After 1 hour the reaction wasconcentrated and dried under high vacuum. The resulting solid wasdissolved in dichloromethane (5 mL) and treated with sodiumtriacetoxyborohydride (1.155 g) and oxetan-3-one (0.262 g) and stirredovernight. The reaction was quenched with saturated NaHCO₃ solution (20mL) and extracted into dichloromethane (2×25 mL). The organic layer wasdried over magnesium sulfate, filtered, and concentrated. Silica gelchromatography (Reveleris 80 g) eluting with a gradient of 0.5% to 3.75%methanol/dichloromethane over 40 minutes (flow=30 mL/min) gave the titlecompound.

Example 357B (4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methanol

To a solution of EXAMPLE 357A (0.59 g) in tetrahydrofuran (5 mL) wasadded lithium aluminum hydride (1.80 mL) at 0° C. The reaction wasremoved from the ice bath and allowed to warm to room temperature. Thereaction was quenched by the dropwise addition of 0.6 ml of waterfollowed by 0.2 ml of 2N aqueous NaOH. The reaction was filtered throughcelite and rinsed with ethyl acetate (50 mL). The mixture and theresidue was loaded onto silica gel (Reveleris 40 g) and eluted using agradient of 0.75% to 7.5% methanol/dichloromethane over 30 minutes(flow=40 mL/minutes) to provide the title compound.

Example 357C3-cyano-4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 357B for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 284A.

Example 357D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-cyano-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 357C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.49-11.14 (m, 1H), 8.17 (d,1H), 8.03 (d, 2H), 7.51 (dd, 3H), 7.43-7.26 (m, 3H), 7.12-6.96 (m, 2H),6.67 (dd, 1H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.55 (t, 2H), 4.45 (t, 2H),4.34 (d, 2H), 3.49 (s, 1H), 3.09 (s, 8H), 2.39-1.66 (m, 14H), 1.39 (s,2H), 0.92 (s, 6H).

Example 3584-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 358A benzyl (4-ethyl-4-hydroxycyclohexyl)methylcarbamate

To a vigorous stirring solution of benzyl(4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 mL) at−78° C. was slowly added 1 M ethylmagnesium bromide (11.48 ml, 11.48mmol) in ether. After completion of the addition, the mixture wasstirred at −78° C. for 2 hours and was warmed to 0° C., and stirred inan ice bath for 30 minutes. The reaction was quenched with a cold NH₄Claqueous solution. The precipitates were filtered off and washed withethyl acetate. The filtrate was concentrated. The residue was dissolvedin dichloromethane and loaded onto Analogix purification system, and waseluted with 0-50% ethyl acetate in dichloromethane to provide the titlecompound.

Example 358B 4-(aminomethyl)-1-ethylcyclohexanol

A mixture of EXAMPLE 358A (500 mg) and 10% Pd/C (100 mg) intetrahydrofuran (15 mL) was stirred under H₂ for 3 hours. The insolublematerial was removed by filtration, and the filtrate was concentrated toprovide the title compound.

Example 358C4-((trans-4-ethyl-4-hydroxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

EXAMPLE 358B (270 mg) and 4-fluoro-3-nitrobenzenesulfonamide (417 mg) intetrahydrofuran were treated with triethylamine (0.8 mL) overnight. Thereaction was quenched with water. The resulting mixture was neutralizedwith diluted aqueous HCl, and extracted with ethyl acetate. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by a reverse phase chromatography, eluting with 40-55%acetonitrile in 0.1% trifluoroacetic acid water to isolate the titlecompound.

Example 358D4-((cis-4-ethyl-4-hydroxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared and isolated as described in Example358C.

Example 358E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 358C in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.35 (s, 1H), 8.56 (d, 2H), 8.05(d, 1H), 7.80 (dd, 1H), 7.45-7.57 (m, 3H), 7.34 (d, 2H), 7.00-7.10 (m,3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.98 (s, 1H), 3.24-3.31(m, 4H), 3.07 (s, 4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95 (s, 2H),1.54-1.73 (m, 5H), 1.35-1.47 (m, 4H), 1.20-1.32 (m, 2H), 1.03-1.18 (m,2H), 0.92 (s, 6H), 0.81 (t, 3H).

Example 3594-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(cis-4-ethyl-4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 358D in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.34 (s, 1H), 8.60 (t, 1H), 8.56(d, 1H), 8.05 (d, 1H), 7.80 (dd, 1H), 7.54 (d, 1H), 7.47-7.52 (m, 2H),7.34 (d, 2H), 7.01-7.10 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d,1H), 3.77 (s, 1H), 3.26 (t, 2H), 3.07 (s, 4H), 2.76 (s, 2H), 2.10-2.26(m, 6H), 1.95 (s, 2H), 1.46-1.61 (m, 5H), 1.28-1.46 (m, 6H), 1.12-1.24(m, 2H), 0.92 (s, 6H), 0.82 (t, 3H).

Example 3604-(4-{[2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 360A ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate

Into a 500 mL round-bottomed flask was added diisopropylamine (7.98 mL)in tetrahydrofuran (233 mL) to give a colorless solution. The mixturewas cooled to −78° C. under N₂ and n-BuLi (2.5 M in hexanes, 22.40 mL)was added. The reaction was stirred for 30 minutes and ethyl1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g) was added. The reactionwas allowed to stir for 1.5 hours upon which time CH₃I (4.38 mL) wasadded. The reaction was allowed to warm to room temperature overnightwith stirring. Water was added and the aqueous layer was extracted withethyl acetate. The combined organics were dried (Na₂SO₄), filtered andconcentrated by rotary evaporation. The residue was purified by normalphase flash column chromatography (Analogix, 0-50% hexanes/ethylacetate).

Example 360B (8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol

In a 500 mL round-bottomed flask was lithium aluminum hydride (1.772 g)in tetrahydrofuran (234 mL) to give a suspension. This suspension wascooled to 0° C. and ethyl8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (10.66 g) was added viaaddition funnel. The reaction was stirred overnight at room temperatureand then cooled back down to 0° C. The excess lithium aluminum hydridewas slowly quenched with 1.8 mL water, 1.8 mL aqueous NaOH (5N) and 5.6mL water. The suspension was stirred until the salts turned white andwas then filtered through a plug of silica gel. The filtrate wasconcentrated by rotary evaporation and the residue was purified byregular phase flash column chromatography (Analogix, 0-75% hexanes/ethylacetate).

Example 360C 8-(methoxymethyl)-8-methyl-1,4-dioxaspiro[4.5]decane

To a 250 mL round-bottomed flask was added NaH (0.902 g) andtetrahydrofuran (37.6 mL) to give a suspension. EXAMPLE 360B was addedas a tetrahydrofuran solution at room temperature. The suspension wasstirred for 30 minutes and then CH₃I (0.611 mL) was added. The reactionwas stirred under N₂ overnight, carefully quenched with brine anddiluted with water and ether. The aqueous layer was extracted with ether(2×) and the combined organics were dried (Na₂SO₄), filtered andconcentrated by rotary evaporation. The residue was purified by flashcolumn chromatography (Analogix, 0-60% hexanes/ethyl acetate).

Example 360D 4-(methoxymethyl)-4-methylcyclohexanone

The title compound was prepared by substituting EXAMPLE 360C for EXAMPLE353B in EXAMPLE 353C.

Example 360E2-chloro-5-(methoxymethyl)-5-methylcyclohex-1-enecarbaldehyde

The title compound was prepared by substituting EXAMPLE 360D for EXAMPLE353C in EXAMPLE 353D.

Example 360F2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-enecarbaldehyde

The title compound was prepared by substituting EXAMPLE 360E for EXAMPLE353D in EXAMPLE 353E.

Example 360G methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 360F for EXAMPLE353E in EXAMPLE 353F.

Example 360H2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 360G for EXAMPLE15G in EXAMPLE 15H.

Example 36012-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-(methoxymethyl)-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

The title compound was prepared by replacing EXAMPLE 3J with EXAMPLE360H and EXAMPLE 11B with EXAMPLE 1F in EXAMPLE 11D. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.68 (s, 1H) 11.43 (s, 1H) 8.45-8.72 (m, 2H)8.04 (d, 1H) 7.80 (dd, 1H) 7.44-7.61 (m, 3H) 7.34 (d, 2H) 6.99-7.20 (m,3H) 6.68 (dd, 1H) 6.39 (dd, 1H) 6.18 (d, 1H) 3.85 (dd, 2H) 3.25-3.30 (m,4H) 3.24 (s, 3H) 3.02-3.17 (m, 6H) 2.72 (dd, 2H) 2.18 (s, 5H) 2.03-2.13(m, 2H) 1.81-1.93 (m, 2H) 1.57-1.67 (m, 2H) 1.47-1.56 (m, 1H) 1.17-1.41(m, 3H) 0.91 (s, 3H).

Example 3614-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 361A(S)-3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methylamino)benzenesulfonamide

The title compound was prepared by substituting EXAMPLE 259E fortert-butyl piperazine-1-carboxylate and 3-oxetanone for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 361B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-({[(2S)-4-(oxetan-3-yl)morpholin-2-yl]methyl}amino)phenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 361A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (500 MHz, pyridine-d₅) δ 13.00 (s, 1H),9.26 (d, 1H), 8.87 (t, 1H), 8.43 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H),7.66 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.96 (d, 1H), 6.75 (dd, 1H),6.54 (d, 1H), 6.48 (m, 1H), 4.64 (m, 4H), 3.93 (m, 1H), 3.89 (d, 1H),3.68 (dt, 1H), 3.53-3.35 (m, 3H), 3.07 (m, 4H), 2.77 (s, 2H), 2.72 (d,1H), 2.44 (d, 1H), 2.26 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.85 (t,1H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 362N-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 362A 3-chloro-4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methoxy)benzenesulfonamide

To a solution of EXAMPLE 341F (300 mg) in N,N-dimethylformamide (10 mL)was added sodium hydride (416 mg) portionwise. The resulting suspensionwas stirred for 15 minutes. 3-Chloro-4-fluorobenzenesulfonamide (425 mg)was added and stirring was continued for 72 hours. The reaction wasquenched with water and the pH was adjusted to ca. 7. The mixture wasdiluted with brine (75 mL) and extracted with methylene chloride. Thecrude product was isolated from the dried methylene chloride layer byconcentration and was purified on silica gel eluted with a 10, 25, 50%ethyl acetate in methylene chloride step gradient to provide the titlecompound.

Example 362BN-({3-chloro-4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 362A for EXAMPLE130C in EXAMPLE 130D. ¹H NMR (400 MHz, pyridine-d₅) δ 13.07 (m, 1H),8.58 (d, 1H), 8.45 (d, 1H), 8.31 (dd, 1H), 8.11 (d, 1H), 7.69-7.67 (m,2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.97 (d, 1H), 6.74 (dd, 1H), 6.52 (m,2H), 5.34 (br s, 2H), 3.82 (d, 2H), 3.06 (m, 4H), 2.77 (s, 2H), 2.25 (m,2H), 2.13 (m, 4H), 1.97-1.85 (m, 7H), 1.82-1.73 (m, 2H), 1.44-1.32 (m,7H), 0.94 (m, 6H).

Example 3634-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 363A4-((4′-fluorospiro[benzo[d][1,3]dioxole-2,1′-cyclohexane]-4′-yl)methoxy)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 350C (495 mg) in N,N-dimethylformamide (6 mL)was added NaH (65% in mineral oil, 320 mg). The mixture was stirred for30 minutes, and then 4-fluoro-3-nitrobenzenesulfonamide (457 mg) wasadded. The mixture was stirred overnight. The mixture was poured overaqueous NH₄Cl and extracted with ethyl acetate (300 mL). The combinedorganic layers were washed with water, brine and dried over Na₂SO₄.After filtration and evaporation of the solvent, the residue was loadedon a silica gel cartridge and was eluted with 30% ethyl acetate inhexane to provide the title compound.

Example 363B4-((1-fluoro-4-oxocyclohexyl)methoxy)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 363A (860 mg) in ethanol (30 mL) was addedconcentrated HCl (10 mL) and the mixture was stirred at 100° C. for 3hours. The mixture was neutralized with solid Na₂CO₃ and extracted withdichloromethane (300 mL) and washed with aqueous NaHCO₃, water, brineand dried over Na₂SO₄. Filtration and evaporation of the solvent gavethe title compound.

Example 363C4-((4-((2-cyanoethyl)(cyclopropyl)amino)-1-fluorocyclohexyl)methoxy)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 363B (200 mg) in dichloromethane (6 mL) wasadded 3-(cyclopropylamino)propanenitrile (64 mg) followed by sodiumtriacetoxyborohydride (184 mg). The mixture was stirred overnight. Thereaction mixture was diluted with dichloromethane (400 mL) and washedwith 2N aqueous NaOH, water, and brine. After drying over Na₂SO₄, themixture was filtered and evaporation of the solvent gave the titlecompound.

Example 363D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-[(2-cyanoethyl)(cyclopropyl)amino]-1-fluorocyclohexyl}methoxy)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 363C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.66 (s, 1H), 8.35 (s, 1H), 8.02 (d, 2H), 7.51(m, 3H), 7.40 (m, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 6.67 (dd, 1H), 6.39(d, 1H), 6.20 (s, 1H), 4.27 (d, 2H), 3.13 (m, 4H), 2.88 (m, 3H), 2.67(m, 4H), 2.09 (m, 10H), 1.49 (m, 9H), 0.93 (s, 6H), 0.45 (m, 4H).

Example 3644-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 364A 6-amino-5-nitropyridine-3-sulfonic acid

6-Aminopyridine-3-sulfonic acid (20 g) in concentrated H₂SO₄ (80 mL) washeated at 50° C. until it was completely dissolved. To this solution wasadded fuming HNO₃ slowly over 20 minutes, so the internal temperaturedid not exceed 55° C. After the addition was complete, the reactionmixture was heated at 50° C. for 1 hour. After it was cooled to roomtemperature, it was poured into 150 g of ice. The mixture was stirredfor another hour. The flask was cooled to 0° C., and was kept at 0° C.for another 2 hours. The solid was collected by filtration, and washedwith cold 1:1 water/ethanol (20 mL), followed by diethyl ether (10 mL).The solid was dried in a vacuum oven overnight to provide the titlecompound.

Example 364B 6-hydroxy-5-nitropyridine-3-sulfonic acid

EXAMPLE 364A (4.0 g) in aqueous HCl (37%, 12 mL) and water (50 mL) wastreated with sodium nitrite (1.19 g) in water (8 mL) dropwise at 0° C.After the addition was complete, the reaction mixture was stirred at 0°C. for 1 hour. The mixture was heated at reflux for 2 hours. Water wasdistilled off to give a dry residue. After the residue was cooled toroom temperature, a solution of 1:1 ethanol/water (20 mL) was added. Theresulting suspension was cooled to 0° C., and kept at 0° C. for 1 hour.The solid was collected by filtration to provide the title compound.

Example 364C 6-chloro-5-nitropyridine-3-sulfonyl chloride

A mixture of EXAMPLE 364B (2.6 g), PCl₅ (5.91 g), and POCl₃ (10 mL) washeated at 120° C. for 4 hours. The initial suspension became a clearsolution. The excess of POCl₃ was distilled off. After it was cooled toroom temperature, the residue was poured into 50 g of crushed ice. Thesolid was extracted into ethyl acetate. The aqueous layer was extractedwith additional ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated to give crudeproduct that was used in the next step without further purification.

Example 364D 6-chloro-5-nitropyridine-3-sulfonamide

EXAMPLE 364C in tetrahydrofuran (10 mL) was cooled to −10° C. To thissolution was added concentrated ammonium hydroxide (0.82 mL) dropwise.The solution was stirred at −10° C. for 10 minutes. The solvent wasremoved under pressure at room temperature. The residue was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate. The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash column chromatography on silica gel using 5-50% ethylacetate in hexanes to provide the title compound.

Example 364E5-nitro-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 364D for4-fluoro-3-nitrobenzenesulfonamide and(tetrahydro-2H-pyran-4-yl)methanamine for(4-fluorotetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 138D.

Example 364F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 364E for EXAMPLE11B in EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.63 (s,1H), 8.93 (s, 1H), 8.73 (d, 1H), 8.69 (d, 1H), 8.00 (d, 1H), 7.54 (d,1H), 7.47-7.48 (m, 2H), 7.35 (d, 2H), 7.05 (d, 2H), 6.68 (dd, 1H), 6.35(dd, 1H), 6.22 (d, 1H), 3.83 (dd, 2H), 3.51 (t, 2H), 3.21-3.27 (m, 2H),3.10 (s, 4H), 2.83 (s, 2H), 1.90-2.27 (m, 12H), 1.58 (dd, 2H), 1.39 (t,2H), 1.18-1.28 (m, 2H), 0.88-0.93 (m, 8H).

Example 3654-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(2-oxaspiro[3.5]non-7-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 365A 7-(azidomethyl)-2-oxaspiro[3.5]nonane

To a 250 mL round-bottomed flask was EXAMPLE 351F (350 mg) intetrahydrofuran (75.0 mL) to give a colorless solution. The solution wascooled to 0° C., triphenylphosphine (2.94 g), diisopropylazodicarboxylate (2.18 mL) and diphenyl phosphorazidate (2.32 mL) wereadded and the reaction was stirred for 30 minutes at room temperature.The mixture was concentrated and purified the residue by regular phaseflash column chromatography (Analogix, 0-20% hexanes/ethyl acetate).

Example 365B 2-oxaspiro[3.5]nonan-7-ylmethanamine

To a 50 mL round-bottomed flask was added 10% palladium on carbon (58.7mg). The flask was flushed with N₂ and EXAMPLE 365A (400 mg) was addedas a methanol solution (10.5 mL). The flask was then flushed severaltimes with H₂ (via balloon) and heated to 45° C. for 2 hours. Thereaction was cooled to room temperature, filtered through celite and thefiltrate was concentrated by rotary evaporation. The residue was used inthe next step without further purification.

Example 365C4-(2-oxaspiro[3.5]nonan-7-ylmethylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 365B for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 365D2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-(2-oxaspiro[3.5]nonan-7-ylmethylamino)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 365C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H) 11.25-11.49 (m, 1H) 8.48-8.66 (m,2H) 8.03 (d, 1H) 7.79 (dd, 1H) 7.41-7.61 (m, 3H) 7.27-7.40 (m, 2H) 7.05(t, 3H) 6.67 (dd, 1H) 6.39 (dd, 1H) 6.18 (d, 1H) 4.29 (s, 2H) 4.19 (s,2H) 3.17-3.27 (m, 2H) 2.99-3.14 (m, 4H) 2.69-2.79 (m, 2H) 2.09-2.28 (m,6H) 2.04 (d, 2H) 1.95 (s, 2H) 1.66 (d, 2H) 1.49-1.61 (m, 1H) 1.29-1.45(m, 4H) 0.93-1.05 (m, 2H) 0.92 (s, 6H).

Example 3664-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 366A tert-butyl (4-cyano-4-methylcyclohexyl)methylcarbamate

To a cooled (−78° C.) solution of tert-butyl(4-cyanocyclohexyl)methylcarbamate (500 mg) in tetrahydrofuran (10 mL)was added lithium diisopropylamide (2.0 mL, 2M in heptane). The mixturewas stirred at −78° C. for 30 minutes before the addition of CH₃I (1mL). The mixture was then stirred and the temperature was allowed towarm to room temperature. The reaction was quenched with aqueous NH₄Cland the mixture was extracted with ethyl acetate (300 mL) and washedwith water, brine and dried over Na₂SO₄. Filtration and evaporation ofthe solvent and silica gel chomatography (40% ethyl acetate in hexane)of the crude material gave the title compound.

Example 366B 4-(aminomethyl)-1-methylcyclohexanecarbonitrile

To a solution of EXAMPLE 366A (480 mg) in dichloromethane (10 mL) wasadded trifluoroacetic acid (10 mL). The mixture was stirred for 3 hours.The mixture was then concentrated under vacuum and was used directly inthe next reaction without further purification.

Example 366C4-((4-cyano-4-methylcyclohexyl)methylamino)-3-nitrobenzenesulfonamide

To a solution of 4-fluoro-3-nitrobenzenesulfonamide (362 mg) intetrahydrofuran (10 mL) was added EXAMPLE 366B (250 mg) andN,N-diisopropylethylamine (2 mL). The mixture was stirred overnight. Themixture was diluted with ethyl acetate (300 mL) and washed with water,brine and dried over Na₂SO₄. Filtration and evaporation of the solventgave the title compound.

Example 366D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 3J for EXAMPLE1E and EXAMPLE 366C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.67 (s, 1H), 11.37 (m, 1H), 8.59 (m, 2H), 8.04(d, 1H), 7.80 (d, 1H), 7.51 (m, 3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04(d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.19 (s, 1H), 3.07 (m, 4H), 2.75(m, 2H), 2.17 (m, 7H), 1.76 (m, 9H), 1.32 (m, 9H), 0.92 (s, 6H).

Example 367{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methylpivalate

This example was prepared by substituting chloromethyl pivalate forchloromethyl butyrate in EXAMPLE 368. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.72 (s, 1H), 8.43 (d, 1H), 8.22 (dd, 1H), 8.01(d, 1H), 7.55 (m, 3H), 7.36 (m, 3H), 7.03 (d, 2H), 6.68 (dd, 1H), 6.41(m, 1H), 6.17 (d, 1H), 5.83 (s, 2H), 4.40 (d, 2H), 3.78 (m, 2H), 3.59(m, 2H), 3.08 (br m, 4H), 2.73 (br s, 2H), 2.18 (br m, 6H), 1.96 (s,2H), 1.84 (m, 4H), 1.39 (m, 2H), 1.00 (s, 9H), 0.92 (s, 6H).

Example 368{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)amino}methylbutyrate

EXAMPLE 37E (500 mg) was dissolved in acetonitrile (3.7 mL) andchloromethyl butyrate (77 mg) and Hunig's base (73 mg) were added. Thereaction was heated under reflux for one day. After cooling and dilutionwith dimethylsulfoxide (4 mL) the reaction was purified by preparativeHPLC using a 250×50 mm C18 column and eluting with 20-100% CH₃CN vs.0.1% trifluoroacetic acid in water, giving the product as atrifluoroacetate salt. The trifluoroacetic acid salt was dissolved indichloromethane (6 ml) and washed with 50% aqueous NaHCO₃. The organiclayer was dried over anhydrous Na₂SO₄, filtered, and concentrated toprovide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ11.72 (s, 1H), 8.43 (d, 1H), 8.22 (dd, 1H), 8.01 (d, 1H), 7.55 (m, 3H),7.36 (m, 3H), 7.03 (d, 2H), 6.68 (dd, 1H), 6.41 (m, 1H), 6.17 (d, 1H),5.83 (s, 2H), 4.40 (d, 2H), 3.78 (m, 2H), 3.59 (m, 2H), 3.08 (br m, 4H),2.73 (br s, 2H), 2.18 (m, 8H), 1.96 (s, 2H), 1.84 (m, 4H), 1.39 (m, 4H),0.92 (s, 6H), 0.75 (t, 3H).

Example 3694-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(²H₈)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 369A methyl4-[(2,2,3,3,5,5,6,6-²H₈)piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate

Into a 40 mL vial were added EXAMPLE 3H (1.55 g) and piperazine-d₈(2.040 g) in dimethylsulfoxide (13 mL). The solution was heated to 85°C. for 2.5 hours, and was then allowed to cool to room temperatureovernight. The mixture was transferred to a 120 mL flask and was cooledto 5-10° C. Dichloromethane (30 mL) was added, then water (10 mL) wasadded via syringe over 5 minutes maintaining temp at no more than 15° C.The layers were separated and the organic layer was washed with water(4×10-15 mL) until pH of aqueous layer was 8-9. The organic layer wasfiltered through Na₂SO₄ and rinsed with dichloromethane (5 mL), andconcentrated to provide the title compound.

Example 369B methyl4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(²H₈)piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate

In a 100 mL round-bottomed flask, EXAMPLE 369A (3.4 g), EXAMPLE 290B(1.321 g) and dichloromethane (3 mL) were added to a 100 mL round bottomflask at room temperature. To a separate 50 mL 3 neck round bottomflask, sodium triacetoxyborohydride (1.330 g) and dichloromethane (12mL) were added to give a slurry. After cooling the 50 mL round bottomflask to 18-20° C., the piperazine adduct/aldehyde solution was addedvia syringe over 5 minutes. The triacetoxyborohydride graduallydissolved to give a clear solution after ˜5 minutes. After an additional10 minutes, the solution became hazy. After 16 hours, the reaction wascooled to 5-10° C. Saturated aqueous NaHCO₃ (12 mL) was added over 5minutes maintaining the temperature at no more than 10° C. The layerswere separated and the organic layer was washed with saturated aqueousNaHCO₃, and 10% NaCl (12 mL), and then filtered through Na₂SO₄ andrinsed with dichloromethane (4 mL). The solution was concentrated on arotovap, and chase concentrated with methanol (40 mL). The resultingsolution was cooled to 5-10° C., and the product precipitated. Thesolution was mixed at room temperature for 30 minutes, then filtered andrinsed with methanol (5 mL), and the product was air dried.

Example 369C4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(²H₈)piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoicacid

The title compound was prepared by substituting EXAMPLE 369B for EXAMPLE15G in EXAMPLE 15H.

Example 369D4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(²H₈)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

To a mixture of EXAMPLE 369C (2.0 g), EXAMPLE 1F (1.1 g) andN,N-dimethylpyridin-4-amine (0.7 g) in dichloromethane (20 mL) was added1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.8 g).The reaction mixture was stirred at room temperature overnight. Thereaction was quenched with N,N-dimethylethane-1,2-diamine (0.6 g) andstirred at room temperature for 3 hours. The mixture was extracted with20% aqueous acetic acid and washed with 5% aqueous NaCl. Methanol (2 mL)and ethyl acetate (18 mL) were added and the precipitate was collectedby filtration to provide the title compound. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.71 (s, 1H), 11.37 (s, br, 1H), 8.60 (t, 1H),8.55 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.47-7.54 (m, 3H), 7.31-7.34(m, 2H), 7.09 (d, 1H), 7.01-7.03 (m, 2H), 6.67 (dd, 1H), 6.39 (dd, 1H),6.19 (d, 1H), 3.83 (dd, 2H), 3.21-3.30 (m, 4H), 3.00-3.10 (s, 4H), 2.75(s, 2H), 2.05-2.24 (m, 6H), 1.95 (s, 2H), 1.80-1.93 (m, 1H), 1.55-1.64(m, 2H), 1.37 (t, 2H), 1.18-1.31 (m, 2H), 0.90 (s, 6H).

Example 3704-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]sulfonyl}benzamideExample 370A5-amino-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide

A mixture of EXAMPLE 364E (0.16 g) and 5% palladium on carbon (0.025 g)in ethanol (5 mL) was treated with a balloon of hydrogen. The reactionmixture was stirred overnight. The solid was filtered off. The filtratewas concentrated. The residue was purified by flash chromatography onsilica gel to give the title compound.

Example 370B3-((tetrahydro-2H-pyran-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-sulfonamide

EXAMPLE 370A (0.085 g) in water (10 mL) was treated with concentratedH₂SO₄ (0.5 mL). The solution was cooled to 0° C. To this solution wasadded NaNO₂ (0.023 g) in water (1 mL) dropwise. The solution was stirredfor 1 hour at 0° C. The reaction mixture was poured into saturatedNaHCO₃ solution, and extracted with ethyl acetate three times. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to give the title compound.

Example 370C2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-((tetrahydro-2H-pyran-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-ylsulfonyl)benzamide

This example was prepared by substituting EXAMPLE 370B for EXAMPLE 11Bin EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.60 (s, 1H),9.11 (s, 1H), 8.92 (d, 1H), 7.96 (d, 1H), 7.55 (d, 1H), 7.45-7.46 (m,1H), 7.42 (s, 1H), 7.36 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.32 (s,1H), 6.22 (s, 1H), 4.63 (d, 2H), 3.80 (dd, 2H), 3.21-3.30 (m, 2H), 3.16(s, 4H), 2.83 (s, 2H), 2.19-2.29 (m, 6H), 1.97 (s, 2H), 1.33-1.41 (m,6H), 0.93 (s, 2H).

Example 3714-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 371A6-((trans-4-hydroxy-4-methylcyclohexyl)methylamino)-5-nitropyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 364D for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 376B for EXAMPLE 138C inEXAMPLE 138D.

The title compound was isolated by reverse phase Gilson Prep HPLC systemwith a Phenomenex prep column (Luna, 5μ, C18(2), 250×21.20 mm, 5 Å)eluting with 20-80% acetonitrile in water with 0.1% TFA.

Example 371B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 371A for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.63 (s,1H), 11.53-10.99 (m, 1H), 8.91 (s, 1H), 8.71 (dd, 2H), 8.01 (d, 1H),7.61-7.44 (m, 3H), 7.44-7.28 (m, 2H), 7.12-6.97 (m, 2H), 6.76-6.61 (m,1H), 6.36 (dd, 1H), 6.21 (d, 1H), 3.92 (s, 1H), 3.48 (t, 2H), 3.10 (s,4H), 2.83 (s, 2H), 2.24 (dd, 6H), 1.96 (s, 2H), 1.37 (ddd, 11H), 1.07(s, 3H), 0.93 (s, 6H).

Example 3724-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-cyano-6-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 372A ethyl 4-fluoro-1-(oxetan-3-yl)piperidine-4-carboxylate

To 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.00 g)was added HCl (4.0M in dioxane, 4.54 mL). After 1 hour the reaction wasconcentrated and dried under high vacuum. The resulting solid wasdissolved in dichloromethane (5 ml) and treated with sodiumtriacetoxyborohydride (1.155 g) and oxetan-3-one (0.262 g) and stirredovernight. The reaction was quenched with saturated NaHCO₃ solution (20mL) and extracted into dichloromethane (2×25 mL). The organic layer wasdried over magnesium sulfate, filtered, and concentrated. Silica gelchromatography (Reveleris 80 g) eluting with a gradient of 0.5% to 3.75%methanol/dichloromethane over 40 minutes (flow=30 mL/minute) gave thetitle compound.

Example 372B (4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methanol

To a solution of EXAMPLE 372A (0.59 g) in tetrahydrofuran (5 mL) wasadded lithium aluminum hydride (1.80 mL) at 0° C. The reaction wasremoved from the ice bath and allowed to warm to room temperature. Thereaction was quenched by the dropwise addition of 0.6 mL of waterfollowed by 0.2 ml of 2N aqueous NaOH. The reaction was filtered throughdiatomaceous earth and rinsed with ethyl acetate (50 mL). The organicswere concentrated and loaded onto silica gel (Reveleris 40 g) and elutedusing a gradient of 0.75% to 7.5% methanol/dichloromethane over 30minute (flow=40 mL/minutes) to give the title compound.

Example 372C5-bromo-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 372B for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 36A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.

Example 372D5-cyano-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 372C for EXAMPLE 36Bin EXAMPLE 36C.

Example 372E2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(5-cyano-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridin-3-ylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 372D for EXAMPLE11B in EXAMPLE 11D. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.58 (s,1H), 8.71 (s, 1H), 8.52 (s, 1H), 7.96 (d, 1H), 7.57 (d, 1H), 7.48-7.30(m, 4H), 7.06 (d, 2H), 6.68 (d, 1H), 6.37-6.22 (m, 2H), 4.65-4.40 (m,6H), 3.58 (s, 1H), 3.12 (s, 6H), 2.84-2.59 (m, 4H), 2.17 (s, 6H), 1.96(d, 6H), 1.41 (s, 2H), 0.93 (s, 6H).

Example 373N-(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)morpholine-4-carboxamideExample 373A morpholine-4-carboxamide

A solution of morpholine-4-carbonyl chloride (2.0 g) in methanol (10 mL)and 7 N NH₃ in methanol (5 mL) was stirred at 45° C. overnight. Themixture was concentrated to give a solid, which was dried under vacuum.

Example 373B N-(2-nitro-4-sulfamoylphenyl)morpholine-4-carboxamide

This example was prepared by substituting EXAMPLE 373A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 24A.

Example 373CN-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenyl)morpholine-4-carboxamide

This example was prepared by substituting EXAMPLE 373B for EXAMPLE 130Cin EXAMPLE 130D. 1H NMR (500 MHz, pyridine-d₅) δ 13.02 (s, 1H), 10.41(s, 1H), 9.27 (d, 1H), 8.81 (d, 1H), 8.50 (dd, 1H), 8.40 (d, 1H), 8.09(d, 1H), 7.65 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.76 (dd, 1H), 6.54(d, 1H), 6.48 (m, 1H), 3.67 (m, 4H), 3.58 (m, 4H), 3.07 (m, 4H), 2.77(s, 2H), 2.26 (t, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94(s, 6H).

Example 3744-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methoxymethyl)cyclohexyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 374A (4,4-diethoxycyclohexyl)methanol

Ethyl 4, 4-diethoxycyclohexanecarboxylate (6.67 g) synthesized accordingto a literature procedure (European Journal of Organic Chemistry, 2008,5, 895) in tetrahydrofuran (60 mL) was treated with 2 M lithium aluminumhydride in tetrahydrofuran (14.5 mL) at 0° C. for 1 hour. Water (3 mL)was slowly added to quench the reaction. The precipitates were filteredoff and washed with ethyl acetate. The filtrate was dried over Na₂SO₄,filtered, and concentrated to provide the title compound.

Example 374B 1,1-diethoxy-4-(methoxymethyl)cyclohexane

EXAMPLE 374A (665 mg) in tetrahydrofuran (20 mL) was treated with NaH(394 mg) for 30 minutes and then CH₃I (0.267 mL) was slowly added. Theresulting mixture was stirred overnight and the reaction was quenchedwith a few drops of water. The mixture was concentrated and the residuewas suspended in water and extracted with dichloromethane. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography, and was eluted with 0-15% ethylacetate in dichloromethane to provide the title compound.

Example 374C 4-(methoxymethyl)cyclohexanone

EXAMPLE 374B (2.2 g) in a mixture of water (3 mL) and acetic acid (12mL) was heated at 65° C. for 2 hours. The reaction mixture wasconcentrated. The residue was mixed with water and saturated aqueousNaHCO₃ and extracted with dichloromethane. The dichloromethane layer wasdried over Na₂SO₄, filtered, and concentrated to provide the titlecompound.

Example 374D 4-(methoxymethyl)cyclohexanecarbonitrile

To a cold (−10° C.) solution of EXAMPLE 374C (1.18 g) andtoluenesulfonylmethyl isocyanide (2.268 g) in dimethoxyethane (3 mL) andabsolute ethanol (0.1 mL) was added (in small portions) potassiumtert-butoxide (2.235 g). The reaction mixture was continued to stir at<5° C. for 30 minutes, warmed to room temperature, heated at 35° C. for30 minutes and then at room temperature for 2 hours. The reactionmixture was concentrated and the residue was dissolved in water-brine,and extracted with dichloromethane. The dichloromethane layer waspurified by flash chromatography, and was eluted with 5% ethyl acetatein dichloromethane to provide the title compound.

Example 374E (4-(methoxymethyl)cyclohexyl)methanamine

To a solution of EXAMPLE 374D (460 mg) in tetrahydrofuran (15 mL) wasadded 2M lithium aluminum hydride in tetrahydrofuran (2.252 mL) slowly.The reaction mixture was stirred at room temperature for 1 hour,refluxed for 1 hour and cooled. 2 ml of 2M aqueous NaOH and water (5 mL)was added. The solid was filtered off and washed with ether. Thefiltrate was concentrated. The residue was mixed with dichloromethane(50 mL) and the resulting mixture was dried over Na₂SO₄ and concentratedto provide the title compound.

Example 374F4-((4-(methoxymethyl)cyclohexyl)methylamino)-3-nitrobenzenesulfonamide

EXAMPLE 374E (450 mg) and 4-fluoro-3-nitrobenzenesulfonamide (693 mg) intetrahydrofuran (10 mL) were stirred overnight. The reaction mixture wasconcentrated and the residue was suspended in a mixture of CH₃CN,methanol and water. The precipitates were collected, washed with waterand dried to give the title compound.

Example 374G2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((4-(methoxymethyl)cyclohexyl)methylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 11D usingEXAMPLE 374F in place of EXAMPLE 11B. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.69 (s, 1H), 11.40 (s, 1H), 8.53-8.61 (m, 2H),8.04 (d, 1H), 7.77-7.82 (m, 1H), 7.47-7.55 (m, 3H), 7.34 (d, 2H),7.02-7.09 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.18-3.27(m, 5H), 3.04-3.14 (m, 5H), 2.75 (s, 2H), 2.11-2.24 (m, 6H), 1.95 (s,2H), 1.69-1.84 (m, 3H), 1.33-1.63 (m, 7H), 0.84-1.05 (m, 9H).

Example 3754-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-chloro-6-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 375A methyl 1-(thiazol-2-yl)piperidine-4-carboxylate

A mixture of methyl piperidine-4-carboxylate (2.045 g), 2-bromothiazole(1.64 g), and Cs₂CO₃ (5.86 g) in dimethylformamide (15 mL) was heated at100° C. overnight. After it cooled to room temperature, the reactionmixture was partitioned between water and ethyl acetate. The organiclayer was separated, and the aqueous layer was extracted with additionalethyl acetate three times. The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatography on silica gel to give the titlecompound.

Example 375B (1-(thiazol-2-yl)piperidin-4-yl)methanol

This example was prepared by substituting EXAMPLE 375A for EXAMPLE 339Ain EXAMPLE 339B.

Example 375C5-chloro-6-((1-(thiazol-2-yl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 375B for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 40A for EXAMPLE 36A inEXAMPLE 36B.

Example 375D2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(5-chloro-6-((1-(thiazol-2-yl)piperidin-4-yl)methoxy)pyridin-3-ylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 375C for EXAMPLE 11Bin EXAMPLE 11D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.65 (s, 1H),8.49 (s, 1H), 8.17 (s, 1H), 8.01 (d, 1H), 7.54 (d, 1H), 7.48-7.49 (m,2H), 7.35 (d, 2H), 7.14 (d, 1H), 7.05 (d, 2H), 6.80 (d, 1H), 6.67 (dd,1H), 6.38 (dd, 1H), 6.21 (d, 1H), 4.28 (d, 2H), 3.92 (d, 2H), 2.98-3.10(m, 6H), 2.86 (s, 2H), 2.30 (m, 4H), 2.03-2.15 (m, 3H), 1.96 (s, 2H),1.96 (s, 2H), 1.82-1.86 (m, 2H), 1.33-1.44 (m, 4H), 0.93 (s, 6H).

Example 3764-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 376A tert-butyl (4-hydroxy-4-methylcyclohexyl)methylcarbamate

A solution of tert-butyl (4-oxocyclohexyl)methylcarbamate (1.00 g) wasdissolved in tetrahydrofuran (20 mL) and cooled to −78° C.Methylmagnesium bromide (4.40 mL) was added dropwise. The reaction wasstirred for 2 hours at −78° C. then allowed to warm to 0° C. and stirredfor 30 minutes. The resulting suspension was quenched with water (10mL), diluted with ether (50 mL), washed with ammonium chloride (25 mL),washed with brine (25 mL), dried over magnesium sulfate, filtered, andconcentrated. Silica gel chromatography (Reveleris 80 g) eluting using agradient of 5% to 50% ethyl acetate/dichloromethane over 30 minutes(flow=60 mL/min) gave the title compound as a ˜2:1 mixture of cis andtrans isomers.

Example 376B 4-(aminomethyl)-1-methylcyclohexanol

To a solution of EXAMPLE 376A (0.75 g) in dichloromethane (3 mL) wasadded a few drops of water followed by trifluoroacetic acid (1.19 mL)and the reaction stirred at room temperature. After stirring for 2hadded added additional trifluoroacetic acid (0.5 mL). After anadditional 4 h the reaction was concentrated and dried under highvacuum. The resulting oily solid was triturated with diethyl ether withsonication. Filtration and washing with diethyl ether gave the titlecompound as a trifluoroacetic acid salt and a mixture of cis and transisomers.

Example 376C6-((cis-4-hydroxy-4-methylcyclohexyl)methylamino)-5-nitropyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 364D for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 376B for(4-fluorotetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 138D. The titlecompound was isolated by reverse phase Gilson Prep HPLC system with aPhenomenex prep column (Luna, 5μ, C18(2), 250×21.20 mm, 5 Å) elutingwith 20-80% acetonitrile in water with 0.1% TFA.

Example 376D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-{[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 376C for EXAMPLE 11Bin EXAMPLE 11D. 1H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.64 (s, 1H),8.91 (s, 1H), 8.72 (d, 1H), 8.70 (d, 1H), 8.01 (d, 1H), 7.47-7.54 (m,3H), 7.35 (d, 2H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.36 (dd, 1H), 6.21 (d,1H), 3.93 (s, 1H), 3.48 (t, 2H), 3.10 (s, 4H), 2.83 (s, 2H), 2.15-2.33(m, 6H), 1.96 (s, 1H), 1.34-1.59 (m, 9H), 1.17-1.24 (m, 2H), 1.07 (s,2H), 0.92 (s, 6H).

Example 3774-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 378D for EXAMPLE1E and EXAMPLE 337M for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz,pyridine-d₅) δ 13.07 (s, 1H), 9.31 (d, 1H), 8.68 (t, 1H), 8.44 (d, 1H),8.37 (dd, 1H), 8.10 (d, 1H), 7.68 (m, 1H), 7.66 (d, 1H), 7.41 (m, 2H),7.09 (m, 2H), 6.92 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.50 (dd, 1H),3.20 (m, 5H), 3.06 (t, 4H), 2.77 (m, 2H), 2.57 (d, 1H), 2.49 (m, 1H),2.17 (m, 6H), 1.86 (m, 5H), 1.69 (m, 4H), 1.40 (s, 3H), 1.23 (m, 5H).

Example 3784-(4-{[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideExample 378A 2-chloro-5-methoxy-5-methylcyclohex-1-enecarbaldehyde

Dimethylformamide (1.298 mL) in dichloromethane (2.0 mL) at −10° C. wastreated dropwise with POCl₃ (1.426 mL) to give a colorless solution. Themixture was stirred 5 minutes and then warmed to room temperature andstirred 30 minutes. The solution was cooled to −10° C., treated dropwisewith a solution of 4-methoxy-4-methylcyclohexanone (1.74 g) indichloromethane (2.5 mL), and stirred for 4 hours at ambienttemperature. The reaction mixture was poured over a mixture of ice and25% aqueous sodium acetate solution. After the ice melted, the reactionmixture was poured into a separatory funnel and extracted with diethylether (4×125 mL). The diethyl ether extracts were washed with NaHCO₃solution and brine, dried (MgSO₄), filtered and concentrated. Theconcentrate was chromatographed on silica gel with 0 to 5% ethyl acetatein hexanes as the eluent.

Example 378B2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-enecarbaldehyde

EXAMPLE 378A (1.55 g), 4-chlorophenylboronic acid (1.542 g), PdOAc₂(0.055 g), K₂CO₃ (2.84 g) and tetrabuylammonium bromide (2.65 g) werecombined in a 50-mL round-bottomed flask equipped with a magnetic stirbar. Water (9.13 mL) was added. The vial was flushed with nitrogen,capped and stirred at 45° C. for 14 hours. The reaction mixture wascooled to room temperature and partitioned between brine and diethylether. The organic layer was washed with brine, dried (MgSO₄), filteredthrough a plug of celite, concentrated and chromatographed on silica gelwith 5 to 20% ethyl acetate in hexanes as the eluent.

Example 378C methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 378B for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 15F for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A except that a small amount ofDMSO was added to the reaction mixture.

Example 378D2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 378C for EXAMPLE15G in EXAMPLE 15H.

Example 378E2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 378D for EXAMPLE1E in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-d₅) δ 13.07 (s, 1H), 9.31(d, 1H), 8.68 (t, 1H), 8.43 (d, 1H), 8.37 (dd, 1H), 8.09 (d, 1H), 7.68(m, 1H), 7.66 (d, 1H), 7.41 (m, 2H), 7.09 (m, 2H), 6.90 (d, 1H), 6.74(dd, 1H), 6.52 (d, 1H), 6.50 (dd, 1H), 3.97 (dd, 2H), 3.30 (td, 2H),3.21 (s, 3H), 3.15 (m, 2H), 3.06 (t, 4H), 2.77 (m, 2H), 2.57 (d, 1H),2.50 (m, 1H), 2.16 (m, 6H), 1.81 (m, 2H), 1.63 (m, 1H), 1.57 (dd, 2H),1.32 (m, 2H), 1.21 (s, 3H).

1.-32. (canceled)
 33. A process for preparing methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidin-1-yl)benzoate(271C):

the process comprising: mixing tert-butyl4-hydroxy-4-(2-(trifluoromethylsulfonyloxy)benzyl)piperidine-1-carboxylate(263D):

with 4-chlorophenylboronic acid, K₃PO₄, and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) in2-methyltetrahydrofuran to produce tert-butyl4-((4′-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidine-1-carboxylate(271A):

mixing 271A with triethylsilane in CH₂Cl₂ and trifluoroacetic acid, toproduce 4-((4′-chlorobiphenyl-2-yl)methyl)-4-fluoropiperidine (271B):

mixing 271B and methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (3H):

in dimethylsulfoxide and Hunig's base to produce 271C.
 34. The processof claim 33, which further comprises preparing tert-butyl4-hydroxy-4-(2-(trifluoromethylsulfonyloxy)benzyl)piperidine-1-carboxylate(263D) by a process comprising: adding tert-butyl4-oxopiperidine-1-carboxylate to a mixture of sodium hydride andtrimethylsulfoxonium iodide in dimethyl sulfoxide and tetrahydrofuran toproduce tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (263A):

adding (2-(benzyloxy)phenyl)magnesium bromide to a solution of 263A andCuI in tetrahydrofuran at 0° C., followed to produce tert-butyl4-(2-(benzyloxy)benzyl)-4-hydroxypiperidine-1-carboxylate (263B):

adding 263B and methanol to Raney Nickel under 30 psi pressure andhydrogen, and mixing to produce tert-butyl4-hydroxy-4-(2-hydroxybenzyl)piperidine-1-carboxylate (263C):

mixing together 263C, N-phenylbis(trifluoromethanesulfonimide), and basein dichloromethane to produce 263D.
 35. The process of claim 33 or 34,which further comprises preparing methyl2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (3H) by a processcomprising: adding lithium hexamethyldisilazide in tetrahydrofuran to5-bromo-1H-pyrrolo[2,3-b]pyridine in tetrahydrofuran followed by addingtriisopropylchlorosilane and mixing to produce5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3F):

adding BuLi to 3F in tetrahydrofuran at −78° C., followed by addingtrimethylborate and allowing the mixture to warm to room temperature toproduce 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (3G):

mixing 3G together with methyl 2,4-difluorobenzoate and K₃PO₄ in diglymeto produce 3H.